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New treatments

Researchers at a hospital in Northern India reported good results in treating New Daily Persistent Headache (NDPH) with repetitive transcranial magnetic stimulation (rTMS).

NDPH is a type of headache that begins suddenly and persists daily without specific features, distinct MRI presentation, or blood test abnormalities. It can present similarly to chronic migraines or chronic tension-type headaches. While published reports suggest NDPH is difficult to treat, this is often not the case. However, patients who do not respond to initial standard treatments may become discouraged.

The Indian researchers conducted a pilot study with 50 NDPH patients who received 10 Hz rTMS sessions on the left prefrontal cortex of the brain for three consecutive days. They found that after 4 weeks:

  • 70% of patients had at least a 50% reduction in headache severity

  • Patients gained an average of 11 headache-free days per month

  • 76% had significant improvements in headache-related disability

  • Depression and anxiety scores also improved significantly

The treatment was well-tolerated, with only minor side effects in a few patients. The benefits seemed especially pronounced in patients who had NDPH that resembled chronic migraine.

I never give the diagnosis of NDPH, but diagnose it as a condition it most resembles and treat the person with a wide variety of available options. Many respond. For those who do not, we offer rTMS, a procedure that uses magnetic fields to stimulate nerve cells in the brain. An electromagnetic coil device is placed against the scalp near the forehead. The coil painlessly delivers a magnetic pulse that stimulates the brain with the goal of reducing headache symptoms. The FDA has approved it for the treatment of depression, anxiety, and OCD. We use it for various neurological conditions, including headaches that do not respond to standard therapies. To treat migraines and other types of pain, we usually stimulate not only the left prefrontal cortex, as was done in this study, but also two additional sites that have been reported to help with pain and migraines. These additional sites are either the motor cortex or the occipital cortex, on both sides.

Sometimes, we obtain a functional magnetic resonance imaging (fMRI) scan to better target rTMS. fMRI is a research procedure that is not available commercially (and is not covered by insurance).

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Two sets of “designer drugs” have been developed based on our understanding of the neurobiology of migraines. The first, sumatriptan (Imitrex), introduced in 1992, was the pioneer in a class of seven triptan drugs, all targeting serotonin mechanisms. Erenumab (Aimovig), which targets the CGRP (calcitonin gene-related peptide) mechanism, was approved by the FDA in 2018. This class now includes four injectable, three oral, and one nasal drug. Additionally, many older drugs, although not specifically developed for migraine treatment, have proven effective for some patients. Despite these numerous options, a significant minority of patients do not respond to any of these treatments.

This is why the development of drugs targeting different parts of the migraine cascade is so promising. Danish neurologists, led by Dr. Mesoud Ashina, have published results from a phase 2 double-blind study of a new drug that blocks PACAP (pituitary adenylate cyclase-activating peptide).

In this study, patients were divided into two groups, receiving an infusion of a placebo or two different doses of the active drug, currently known as Lu AG09222, developed by the Danish company Lundbeck. In the final analysis, the reduction in migraine days was compared between 94 patients who received a placebo and 97 patients who received the higher dose of the active drug. The higher dose significantly reduced the number of migraine days in the month following the infusion (6.2 vs. 4.2 days reduction). The side effects reported were mild and infrequent.

Phase 2 studies are relatively small and short in duration. The FDA typically requires two large parallel studies involving a total of 1,000 or more patients before considering approval. Therefore, even if Lu AG09222 is found to be safe and effective, it may not receive approval for another 2-3 years.

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Long COVID, also known as post-COVID conditions, can present with a wide range of symptoms that persist for weeks or months after the initial COVID-19 infection. The most common symptoms of long COVID include:

Neurological Symptoms

  • Headaches
  • Difficulty thinking or concentrating, often referred to as “brain fog”
  • Memory problems
  • Changes in smell or taste

Psychological Symptoms

  • Depression or anxiety
  • Mood changes

Other Symptoms

  • Fatigue or tiredness that interferes with daily life
  • Shortness of breath or difficulty breathing
  • Cough
  • Chest pain or heart palpitations
  • Sleep problems
  • Dizziness when standing up (orthostatic hypotension)
  • Joint or muscle pain
  • Fever
  • Stomach pain or other gastrointestinal issues
  • Changes in menstrual cycles

There is evidence of persistent inflammation in people with long COVID. This inflammation of blood vessels, brain tissues, and other organs is likely the cause of all of the above symptoms.

Receiving a COVID vaccination may prolong the symptoms of long-term COVID-19 in people who have already contracted COVID and now suffer from long COVID. However, vaccines seem to reduce the risk of severe COVID and long COVID.

Unfortunately, we do not have any proven therapies for long COVID. However, it is very important to make sure that nutritional deficiencies do not contribute to long COVID symptoms. I often find a deficiency of vitamin B12 and other B vitamins, vitamin D, magnesium, CoQ10, omega-3 fatty acids, zinc, and others. I recommend looking at your test results yourself since doctors may glance at the report and tell you everything is fine if nothing is flagged. The normal ranges for vitamins are too wide, and if you are at the bottom of the normal range, you are probably deficient. For example, vitamin B12 levels are considered normal between 200 and 1,200. Most neurologists will tell you that your level should be above 500. The same applies to RBC magnesium level – normal is 4.0 to 6.4, but you need to be above 5. Vitamin D should be well above 40, while 30 is still considered normal.

Another supplement I often recommend is NAC. A small study by Yale neurologists showed that 600 mg of NAC improved working memory, concentration, and executive functions. NAC helps the body produce glutathione, an important antioxidant. We sometimes give glutathione infusions along with other vitamins.

Supplements that reduce inflammation include ginger and turmeric extracts.

For brain fog and other neurological symptoms, we have had some success with transcranial magnetic stimulation (TMS). Other neurostimulation methods, such as tDCS, are also worth trying.

Some patients benefit from intravenous infusion of immune globulin, which is approved for some types of neuropathies.

Low-dose naltrexone (LDN) may also help, but no studies prove this.

Probiotics can help people with gastrointestinal symptoms.

Stimulants can be tried to treat fatigue and brain fog. They can also help with depression.

For headaches, we often give Botox injections.

Depression can be treated with antidepressants or TMS.

Some people respond well to physical therapy, acupuncture, herbs, meditation, cognitive-behavioral therapy, and other mind-body techniques.

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The use of focused ultrasound to treat brain disorders was one of the topics discussed at the 2024 NYC Neuromodulation Conference in NYC.

Coincidentally, a study on this topic was published last month by Jan Kubanek and his colleagues in Pain, the journal of the International Association for the Study of Pain: “Noninvasive targeted modulation of pain circuits with focused ultrasonic waves”.

Researchers developed a technique that targets the anterior cingulate cortex, a deep brain region involved in processing pain. By using focused ultrasound, this region can be modulated without surgery. This breakthrough has the potential to revolutionize pain management.

Twenty patients with chronic pain participated in a randomized crossover trial. They received two 40-minute sessions of either active or sham stimulation and were monitored for one week. The results were remarkable:

  • 60% of patients experienced a significant reduction in pain on day 1 and day 7 after active stimulation.
  • Sham stimulation only benefited 15% and 20% of patients, respectively.
  • Active stimulation reduced pain by 60.0% immediately after the intervention and by 43.0% and 33.0% on days 1 and 7.
  • Sham stimulation only reduced pain by 14.4%, 12.3%, and 6.6% on the same days.

The stimulation was well tolerated and the side effects were mild and resolved within 24 hours.

Since we have been using transcranial magnetic stimulation (TMS) to treat refractory migraines and other neurological conditions, it was good to read this part of the authors’ conclusion:

“The ultrasonic intervention is conceptually related to TMS applied to the motor cortex, which can provide improvements in chronic pain in certain groups of patients. The key difference is that ultrasonic waves can directly modulate the deep brain regions involved in chronic pain, including the anterior cingulate cortex. Transcranial magnetic stimulation is believed to modulate deep brain regions only indirectly, which may contribute to its variable response and the need for frequent re-administrations. Nonetheless, the effects of both modalities may be complementary, and their combined application may provide stronger effects than either approach alone.”

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Functional MRI (fMRI) studies have shown that people with migraines have altered functional connectivity and activation patterns in pain-processing brain regions like the insula, thalamus, somatosensory cortex, as well as visual cortex. Some patients also have changes in the default mode and salience networks involved in attention and stimulus processing.

A study published this month by Chinese researchers in the Journal of Headache and Pain reports on connectivity changes in people with vestibular migraines.

They found abnormal resting-state functional connectivity in brain regions involved in multi-sensory and autonomic processing as well as impaired ocular motor control, pain modulation, and emotional regulation.

Until now, there has been little practical application for fMRI findings. However, with the help of Omniscient Neurotechnology, we have just started using fMRI data to better target our treatment with transcranial magnetic stimulation (TMS). TMS applied to motor and visual cortices has been reported to help relieve migraine headaches. We have also found it effective in a significant proportion of patients who did not respond to various other treatments. We have not yet accumulated enough data to determine if fMRI-guided TMS treatment is superior to TMS administered over a predetermined set of targets.

The main obstacle to wider use of TMS in clinical practice is the cost. TMS is approved by the FDA and is covered by insurance for the treatment of anxiety and depression, but not migraines or pain. fMRI is an expensive research tool and is also not covered by insurance. Hopefully, the NIH and other research foundations will provide the funds needed to study this promising treatment.

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Nolan Williams has been at the forefront of developing breakthrough TMS protocols for the treatment of depression and other psychiatric indications. It was very stimulating and informative to discuss techniques, protocols, indications, and research into TMS for various neurological and psychiatric indications with the members of Nolan Williams’ lab Greg Sahlem and Ika Kaloiani. Thank you for sharing your knowledge.

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Repetitive transcranial magnetic stimulation (rTMS) is approved by the FDA for the treatment of depression and anxiety. We have been using it to treat migraine headaches and other neurological conditions that are not responsive to standard therapies. Improvement in headaches and pain may be at least in part due to improvement in depression. However, additional mechanisms play a role since we see patients who are not depressed but whose pain improves with rTMS.

A new study by Chinese and Australian researchers published in Pain suggests that opioid mechanisms (endorphins, encephalin, and other peptides) may underlie the mechanism of pain relief produced by rTMS.

This was a double-blind, placebo-controlled study. 45 healthy participants were randomized into 3 groups: one receiving rTMS over the primary motor cortex (M), dorsolateral prefrontal cortex (DLPFC), or sham stimulation. Experimental pain was induced by applying capsaicin (hot pepper extract) over the skin of the right hand followed by application of heat.

Participants received intravenous naloxone (an opioid receptor antagonist) or saline before the first rTMS session to block or allow opioid effects, respectively. After 90 minutes to allow naloxone metabolism, participants received a second rTMS session.

For the M1 group, naloxone abolished the analgesic effects of the first rTMS session compared to saline. Pain relief returned in the second session after naloxone was washed out of the body. For the DLPFC group, only the second prolonged rTMS session induced significant analgesia in the saline condition compared to naloxone. rTMS over M1 selectively increased plasma ?-endorphin levels, while rTMS over DLPFC increased encephalin levels.

The results suggest that opioid mechanisms mediate rTMS-induced analgesia. The specific opioid peptides and rTMS dosage requirements differ between M1 and DLPFC stimulation.

However, these results are far from definitive. The study was small and the study protocol was complicated (e.g. using a double dose of rTMS to DLPFC), which increases the likelihood of an error. Also, these results apply to conditions of acute pain. In patients with chronic pain and headaches, rTMS likely provides relief by improving network connectivity between different parts of the brain.

 

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A new report suggests that CGRP-blocking drugs (CGRP-A) are safe in pregnancy.

In the latest study, Swiss doctors examined the World Health Organization’s pharmacovigilance database and looked at reporting differences between CGRP drugs and triptans.

Triptans (drugs like sumatriptan or Imitrex and six others) were introduced over 30 years ago.  We know from pregnancy registries, retrospective, and prospective observational studies that triptans are safe in pregnancy.

The WHO database had 467 safety reports of exposure to CGRP-A in pregnancy. Of these, 386 were reports of exposure to CGRP monoclonal antibodies (mAbs), 76 to gepants, and 5 to both. The authors found “…no signals of increased reporting with CGRP-A compared to triptans in relation to pregnancy”.

CGRP drugs represent a major breakthrough in treating migraine headaches. A large proportion of migraine sufferers are women of childbearing age. We always have to consider the effect of a drug on the developing fetus. Erenumab (Aimovig), the first drug in this category was introduced almost six years ago. This is a relatively short period to assess the safety of a drug in pregnant women and the current report is not a definitive proof of safety.

There might be a difference in safety between oral CGRP antagonists (gepants), which are small molecules and injectable mAbs, which are large molecules. Gepants have the advantage of being completely washed out of the body within a few days of stopping them.  Monoclonal antibodies are injected every one or three months and can take a few months to completely leave the body. However, mAbs, being larger, cannot cross the placenta in the first trimester. So if a mAb is stopped at the beginning of pregnancy the exposure to the fetus will be small.

The gepants include ubrogepant (Ubrelvy), rimegepant (Nurtec), atogepant (Qulipta), and a nasal spray, zavegepant (Zavzpret). The monoclonal antibodies are erenumab, fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti).

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We use a neuronavigation system from Soterix (on the left) for precise targeting of transcranial magnetic stimulation (TMS). And we use the most advanced TMS machine from MagVenture (on the right) to treat chronic pain, migraines, fibromyalgia, and other neurological conditions.

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Medication overuse or rebound headaches can occur as the result of excessive intake of caffeine, opioid analgesics, and short-acting barbiturate drug, butalbital (contained in Fioricet, Esgic and similar drugs). These three substances not only worsen migraine headaches, they are also addictive.  Two of my patients with medication overuse headaches were able to stop the offending drugs with the help of repetitive transcranial magnetic stimulation (rTMS).

One patient, a 51-year-old man, had his migraines under control with Botox and infusions of eptinezumab (Vyepti) until he sustained a head injury with a skull fracture. His migraines worsened and he became disabled. A variety of therapies failed to reduce his pain. His pain was partially relieved by 60 mg of oxycodone a day, although he still was unable to work. After six weekly sessions of rTMS he was able to start reducing his oxycodone intake and after eight, he completely stopped it. He was able to return to work with the help of injections of fremanezumab (Ajovy).

Another patient, a 50-year-old woman, had been taking butalbital with caffeine and acetaminophen (Fioricet) for 20 years. The number of pills increased over time and for the previous several years, she had been taking 10 to 12 tablets every day. She was also receiving Botox injections, infusions of eptinezumab, and taking rizatriptan (Maxalt), 10 mg three times a day as well as 60 mg of nortriptyline, 12 mg of tizanidine nightly and atogepant, 60 mg. She had tried a wide variety of other treatments but was unable to reduce her Fioricet intake. Despite her persistent migraines, she was able to take care of her family. After three weekly sessions of rTMS she reduced her Fioricet intake to 3-4 a day, by the third month she was taking one a day, and after 6 months she was completely off it. She was also able to stop atogepant and tizanidine and reduced her nortriptyline to 25 mg.

In addition to helping relieve pain and migraines, rTMS has shown promise in the treatment of addiction, particularly in addressing withdrawal symptoms, depression, and cravings. While the use of rTMS for addiction is still relatively recent and not yet FDA-approved, some studies have demonstrated positive outcomes. For instance, a double-blind study showed that individuals receiving rTMS therapy for cocaine addiction had a higher rate of abstinence compared to those who received standard treatment. rTMS for addiction is still considered experimental, and more research is needed to fully understand its long-term effects and optimal treatment parameters.

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Neurologists frequently find themselves managing patients resistant to standard treatments due to limited proven therapies for many neurological conditions. Some patients cannot tolerate or have contraindications to medications, particularly for such common disabling conditions like migraine and chronic pain. 

One promising treatment is transcranial magnetic stimulation (TMS). It is a proven procedure for anxiety, depression, obsessive-compulsive disorder (OCD), smoking cessation, and acute migraines. TMS utilizes magnetic fields to stimulate nerve cells in the brain that are underactive or reduce the excitability of overactive cells. TMS can change the flow of information between different parts of the brain in various neurological conditions. Published reports show the potential benefit of TMS in fibromyalgia, neuropathic pain, cluster headaches, facial pain, trigeminal and other neuralgias, back pain, insomnia, memory disorders, tinnitus, post-concussion syndrome, post-traumatic stress disorder (PTSD), restless leg syndrome, and long COVID. The evidence for the efficacy of TMS for these neurological disorders, however, is still limited.

Single-pulse TMS is approved by the FDA for the acute treatment of migraines with aura. The patient uses a portable device during the aura phase to self-administer a single pulse of TMS to the back of the head. This can abort the attack. Repetitive TMS (rTMS) has been studied for the prevention of migraines and other types of pain. It appears effective, but compared to depression trials, migraine studies were relatively small and the FDA has not cleared rTMS for the treatment of migraines. This means that insurance companies are not likely to pay for this “off-label” use of TMS.

rTMS is generally considered safe and well-tolerated, with side effects typically mild and temporary, including scalp discomfort, headaches, and facial twitching. More serious side effects like seizures and mania are very rare. 

Before starting TMS, patients undergo a physical and mental health evaluation. The coil placement and dose are determined in the first session. During a TMS session, patients sit in a comfortable chair with earplugs. An electromagnetic coil is positioned near the scalp, delivering short magnetic pulses to specific brain regions involved in processing pain and other information. Patients feel and hear rapid tapping on their scalp that continues, on and off. Patients are awake and alert during the entire procedure. There are no limitations to activities before or after the treatment.

Treatment length varies from 20 to 45 minutes, depending on the stimulation pattern and number of sites stimulated. The frequency of treatments also varies – anywhere from daily for several weeks, to once a week. After the initial period of more frequent sessions, some patients require weekly or monthly sessions to maintain the effect. It may take a few weeks to see noticeable effects. 

TMS is a good choice for people who have not responded to multiple standard therapies, people who do not want to take drugs, those who also suffer from depression and anxiety, and pregnant women. Sufficient evidence suggests that TMS is as safe in children as it is in adults, with studies indicating its effectiveness in treating depression in adolescents.

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The annual course, “The Shifting Migraine Paradigm 2024” will be held February 15-17, 2024 at the Plaza San Antonio Hotel & Spa. This three-day conference offers an excellent update on the treatment of migraine and other headaches.

It is always an honor to be invited to speak at this event. The topic of my presentation is Supplements and Medical Foods.

 

 

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