Author: Rachael Hansford

NHS England has accepted the recommendation of the Clinical Priorities Advisory Group to roll out LITT (laser interstitial thermal therapy) on the NHS. LITT is a laser treatment for epilepsy offering a less invasive alternative to conventional neurosurgery. It is a stereotactic procedure with the potential for seizure reduction results similar to those of open resection, with fewer side-effects or complications.

LITT allows for individualised neurological treatment with a small wound, a much faster recovery time, less pain, and minimal risk of infection, adverse neurocognitive deficits, or other side effects.

This pioneering laser beam treatment for epilepsy patients is life-changing and will offer hope to hundreds of people every year who have not had success in preventing seizures with traditional drugs. By replacing invasive neurosurgery with a cutting-edge laser therapy, allowing clinicians to better target the parts of the brain causing the epilepsy, we not only dramatically reduce risks to these patients, but drastically reduce their recovery time both in and out of hospital.

The treatment is yet another example of how the NHS continues to deliver on its NHS Long Term Plan commitment to secure the latest medical innovations for patients while also using our commercial means to ensure value for money.

Professor Sir Stephen Powis, NHS national medical director

Find the clinical commissioning policy here.

NICE has published draft guidance stating that although Translarna (also known as ataluren) is clinically effective and an innovative treatment, there is doubt as to its cost effectiveness. NICE’s draft recommendation is that people currently receiving Translarna should continue to have access to it until they and their NHS clinician consider it appropriate to stop, but that it shouldn’t be provided for new patients after January 2023.

On 30 September 2022, NICE published its draft guidance on Translarna (also known as ataluren). Translarna is used to treat Duchenne muscular dystrophy with a nonsense mutation in the dystrophin gene and is currently available through a Managed Access Agreement (MAA), which ends in January 2023. Duchenne muscular dystrophy affects around 2,500 people in the UK, and it is estimated that approximately 10% of these people carry a nonsense mutation in the dystrophin gene. 

The draft guidance recognises the clinical effectiveness of Translarna and that the treatment is likely to slow the progression of Duchenne muscular dystrophy. It also recognises that Translarna has a positive impact on the lives of people receiving it and on caregivers. However, at this stage NICE is concerned about the cost effectiveness of the treatment.

This has led to the draft guidance recommending that while anyone currently receiving Translarna should continue to do so after the MAA ends in January 2023, the NHS should not provide the treatment to newly diagnosed patients after that date. This draft recommendation is now subject to consultation until 21 October 2022, with a final decision likely by January 2023. 

NICE guidance is usually mirrored in Wales and Northern Ireland. In Scotland, Translarna is available through the ultra-orphan pathway until early 2024.

The uncertainties around the cost-effectiveness of Translarna highlighted in the draft guidance include how quality-of-life differences between people receiving Translarna and other people with Duchenne muscular dystrophy are measured, how caregivers’ quality of life is measured, and the age at which people are likely to start receiving Translarna.

Action Duchenne, MDUK and Duchenne UK will be submitting a joint response to the NICE consultation and will shortly highlight key areas of input needed.

Take part in the NICE consultation by visiting the ataluren section of the NICE website. 

Related articles

First Publication of Real-World Data Showing Translarna (ataluren) Significantly Preserves Ability to Walk for Longer in Children with Duchenne Muscular Dystrophy | ACNR

What is the role for preconception carrier screening in neurology? | ACNR Journal

Investigation of hereditary muscle disorders in the genomic era | ACNR

Sir William Gowers (1845-1915): a centenary celebration, with an examination of his comments on cognitive dysfunction | ACNR

New research could lead to treatments that halt the advance of Parkinson’s disease. Study from University of Haifa could have significant implications for how Parkinson’s disease is treated following a breakthrough in identifying common neural processes for the first time.

A new study conducted by University of Haifa has identified processes that may help prevent the spread of Parkinson’s disease. The study, published in NJP Parkinson’s Disease, has for the first time identified neural processes that are common to various different types of the disease. 

The processes relate to the ability of cells to connect to the extracellular matrix and their capacity to create new synopses. Thanks to the use of the innovative Sendai Reprogramming technique, the researchers were able to show for the first time that even in sporadic Parkinson patients for which no animal model has yet been developed, these processes are also impaired. 

Parkinson’s patients suffer from massive loss of nerve cells in the area of the brain known as the Substantia nigra, which is packed with dopaminergic neurons. Dopamine is required in the process of transfer of messages between brain cells and plays a key role in the ability to perform motor actions properly. One of the problems in the research – and development of drugs – is the fact that only 15 percent of Parkinson’s cases are caused by known genetic factors, while 85 percent are defined as “sporadic.” Accordingly, it is only possible to create a model for the disease in animals relating to those 15 percent of the cases.

Most of the current studies were undertaken on a small number of familiar Parkinson’s mutations caused by genetic factors, since it is not possible to create models for sporadic forms of the disease. Thanks to the ability to create induced pluripotent stem cells for patients with “sporadic” disease, we managed to show for the first time the presence of impaired neural and cellular mechanisms in a similar manner across all the types of disease we examined.

Study author Dr. Shani Stern, a senior lecturer at the University’s Sagol Department of Neurobiology.

In recent years, however, a method has been developed based on the “reprogramming of mature cells into induced pluripotent stem cells.” According to this method, which was used in the current study, the researchers take cells from specific individuals, reprogramme them into stem cells, and then differentiate them as cells of a different type carrying the same genetic load of the individual from whom they were taken.

In the current instance, Dr. Stern along with Prof. Fred Gage from the Salk Institute; Prof. Alexis Brice from ICM, Paris; Prof. Juergen Winkler from FAU, Germany; and Prof. Irit Sagi from the Weizmann Institute worked on skin cell samples taken from nine patients suffering from Parkinson’s disease. 

Some of the patients were diagnosed with genetic mutations while others had the “sporadic” disease. The skin cells were “restored” to stem cells, which the researchers then differentiated into dopaminergic neurons, so that the cells carried the genetic load of each specific patient and were effectively “sick” with the same type of Parkinson’s disease as that participant. The process was also used for four healthy participants constituting a control group. In the second stage, the researchers sequenced the RNA expressed in the dopaminergic cells and prepared an electrophysiological profile of the cells, measuring electric currents and potentials in the nerve cells.

The study found additional evidence of a possible damage to the structures of the extracellular matrix – a decline in the quantity of the proteins that build the matrix – in both the genetic and sporadic form of the disease. It likely leads to the emergence of an unstable structure that in turn causes instability, disconnection, and death in the cells. The researchers also found a decline in the synaptic activity responsible for the transmission of neural messages to the target cells among all the Parkinson’s patients in the study. “It seems that one of the results of the decline in matrix proteins is a decline in synaptic activity and in the ability of the cells to create functional synapses,” Dr. Stern noted.

The dopaminergic neurons we examined were derived from patients through the reprogramming which rejuvenates them into young cells. In other words, we can see changes in the electric activity, genes, and proteins of the extracellular matrix even when the cells are young. This implies that these changes exist in Parkinson’s patients long before they are aware of a disease process that is occurring in their brain. If we perform this sequencing in a young person and find a similar picture to that found among people who have developed Parkinson’s disease, we can assume that this individual will develop the disease at a later stage. 

Dr Stern

“Currently, most of the treatments are intended to prevent the exacerbation of the disease rather than to prevent it. If we can identify the potential to develop Parkinson’s disease at an early stage and develop treatments that can halt the advancement of the disease, we will be able to start preventative treatment at a stage when the nerve cell mortality is limited. This will allow us to significantly slow down the progression of the disease,” Dr. Stern concluded.

• Two separate analyses^1,2 presented at the Migraine Trust International Symposium (MTIS) demonstrate the effectiveness of AJOVY▼(fremanezumab) for the treatment of migraine in patients with migraine and co-morbid depression
• Depression and anxiety are common co-morbidities experienced by around half of all patients with migraine^3,4  and are associated with more pain, disability and a reduced quality of life^1,2
• AJOVY▼(fremanezumab) has been shown to be an effective migraine preventive treatment in a range of patients including those with depression and anxiety^5,6,7

Teva Pharmaceutical  Industries Ltd. announced on 8th September 2022 the results of two studies^1,2 presented at the Migraine Trust International Symposium (MTIS) in London, UK, which demonstrate the efficacy of AJOVY▼ (fremanezumab) in migraine patients who also experience depression or anxiety.  AJOVY▼ (fremanezumab) is indicated for the prevention of migraine in adults with at least 4 migraine days per month.⁸

In both studies, quarterly and monthly dosing of fremanezumab demonstrated efficacy in reducing monthly migraine attacks by more than 50% compared to placebo.^1,2 This is an important outcome because psychiatric disorders are a common co-morbidity in patients suffering from migraine. Population-based samples of people with migraine show up to 47% have co-morbid depression, and up to 58% have co-morbid anxiety⁴ with many patients experiencing both psychiatric conditions.

The first study¹ relating to this patient cohort was led by Richard Lipton MD, Department of Neurology, Psychiatry and Behavioural Sciences at Albert Einstein College of Medicine, New York.  This study is an analysis of pooled data from two previous six-month studies: HALO and FOCUS. The new study to be presented at MTIS sets out to analyse the efficacy of quarterly or monthly dosing of fremanezumab versus placebo in people with migraine and one or more psychiatric co-morbidities.¹

Results at three months showed that 32% of patients on quarterly fremanezumab (n=61) and 36% of patients on monthly fremanezumab (n=75) achieved a ≥ 50% reduction in monthly-migraine-days (MMD) compared to 19% of those taking placebo (n=42), and that proportion increased after continuing or switching to fremanezumab at month six.¹

The second study² is a sub-analysis of patients from the double-blind, placebo-controlled phase 3b FOCUS study led by Patricia Pozo-Rosich, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Research, Barcelona. The FOCUS study set out to evaluate the efficacy of quarterly or monthly fremanezumab in chronic or episodic migraine patients who had experienced an inadequate response to two to four classes of prior preventive migraine medication. The sub-analysis evaluated treatment efficacy on a sub-group of the migraine patients who had co-morbid depression.²

Reductions were observed in both monthly-migraine-days and monthly-headache-days with both quarterly and monthly fremanezumab compared with placebo. Differences were also seen in patient-reported depressive symptoms using a PHQ-9 questionnaire – a brief self-reporting instrument incorporating recognised depression criteria and other depressive symptoms⁹ suggesting that effective treatment of migraine can also positively impact depressive symptoms in patients with this co-morbidity.

Clinicians are becoming increasingly aware of the impact that co-morbidities can have on the management of migraine patients. I believe that we need to move towards more personalised treatment decisions that are tailored to the patient’s profile and co-morbidities. As depression and anxiety are commonly associated with migraine, it will be very important for treatments to demonstrate efficacy and safety in migraine patients with these particular co-morbidities.

Dr. Richard Lipton

Details of enrolment progress into the UNITE study were also revealed at MTIS.¹⁰ The 28-week study, led by Dr. Richard Lipton and supported by Teva, will be assessing the efficacy and safety of fremanezumab in adult patients with chronic and episodic migraine and major depressive disorder.  

Commenting on the study, Dr. Lipton said: “We are pleased to report that a total of237 patients have so far enrolled in the UNITE study with 19% from the U.S., 61% from Europe, and 20% from the rest of the world. Assessing the efficacy of fremanezumab in patients with migraine and major depressive disorder will help inform treatment decisions to improve care in this important patient population. We look forward to sharing the results in due course.”

Dr. Dieter Schultewolter, Vice President of Global Medical Affairs Neuroscience at Teva, said: “Teva is strongly committed to supporting further research into the role of fremanezumab in managing the full spectrum of migraine patients, including those who suffer from co-morbid depression and anxiety. We see this as an important step towards a much needed personalised treatment approach for people suffering from migraine in the future.” 

References

1. Lipton et al. Efficacy of Quarterly and Monthly Fremanezumab in Patients With Migraine and Psychiatric Comorbidities. Abstract accepted for MTIS 2022. MTIS2022-229 
2. Pozo-Rosich et al. Fremanezumab Efficacy in Migraine Patients With Prior Inadequate Response to ≥3 Preventive Migraine Medication Classes and Depressive Symptoms. Abstract accepted for MTIS 2022. MTIS2022-230
3. Lanteri-Minet et al. Anxiety and depression associated with migraine: Influence on migraine subjects’ disability and quality of life, and acute migraine management. Pain. 2005; 118: 319- 326.
4. Minen et al. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 2016; 87: 741- 749.
5. Lipton et al. Long-Term Efficacy of Fremanezumab in Patients with Chronic Migraine and Comorbid Moderate to Severe Depression. Presented at the American Academy of Neurology 61st Annual Meeting Philadelphia, Pennsylvania, USA May 4–10, 2019.  P144
6. Winner et al. Long-Term Efficacy of Fremanezumab in Chronic and Episodic Migraine Patients Who Failed at Least One Prior Migraine Preventive Medication: Results of a 1-Year Study. Presented at the American Headache Society 61st Annual Scientific Meeting, Philadelphia, Pennsylvania, USA July 11–14, 2019. P151
7. Silberstein et al. Long-Term Efficacy of Fremanezumab in Chronic and Episodic Migraine Patients with Acute Medication Overuse at Baseline: Results of a 1-Year Study. Presented at the American Headache Society 61st Annual Scientific Meeting, Philadelphia, Pennsylvania, USA July 11–14, 2019. P107
8. Ajovy EU SmPC  https://www.ema.europa.eu/en/documents/product-information/ajovy-epar-product-information_en.pdf [accessed 26 August 2022]
9. PHQ-9 assessment tool. https://www.apa.org/pi/about/publications/caregivers/practice-settings/assessment/tools/patient-health [accessed 26 August 2022]
10. Lipton et al. A Phase 4 Study of Fremanezumab for Preventive Migraine Treatment in Patients With Major Depressive Disorder: Baseline Patient Characteristics in UNITE.  Abstract accepted for MTIS 2022. MTIS2022-231

About AJOVYq (fremanezumab-vfrm) injection
AJOVY is indicated for prophylaxis of migraine in adults who have at least 4 migraine days per month. AJOVY is available as a 225 mg/1.5 mL single dose injection in a pre-filled syringe or, in some countries, in a pre-filled pen. Two dosing options are available: 225 mg once monthly administered as one subcutaneous injection (monthly dosing), or 675 mg every three months (quarterly dosing), which is administered as three subcutaneous injections. AJOVY can be administered either by a healthcare professional or at home by a patient or caregiver. No starting dose is required to begin treatment. AJOVYq European SmPC can be found here.

▼This medicinal product is subject to additional monitoring. Adverse events should be reported. Reporting forms and information can be found at http://www.hpra.ie. Adverse events should also be reported to Teva UK Limited on +44 (0) 207 540 7117 or medinfo@tevauk.com

Gene variants associated with a person’s blood type may be linked to their risk of early stroke, according to a new meta-analysis published in the August 31, 2022, online issue of Neurology^®, the medical journal of the American Academy of Neurology. The meta-analysis included all available data from genetic studies that included young adult ischaemic stroke, which is caused by a blockage of blood flow to the brain.

“Non-O blood types have previously been linked to a risk of early stroke, but the findings of our meta-analysis showed a stronger link between these blood types with early stroke compared to late stroke, and in linking risk mostly to blood type A,” said study author Braxton D. Mitchell, PhD, MPH, of University of Maryland School of Medicine in Baltimore.

Specifically, our meta-analysis suggests that gene variants tied to blood types A and O represent nearly all of those genetically linked with early stroke. People with these gene variants may be more likely to develop blood clots, which can lead to stroke.

Braxton D. Mitchell

The meta-analysis involved a review of 48 studies on genetics and ischaemic stroke from North America, Europe and Asia. The studies included 16,927 people with stroke and 576,353 people who did not have a stroke. Of those with stroke, 5,825 people had early onset stroke and 9,269 people had late onset stroke. Early onset stroke was defined as an ischaemic stroke occurring before age 60 and late onset stroke was older than 60.

Researchers looked across all the chromosomes to identify genetic variants associated with stroke. They found a link between early stroke and the area of the chromosome that includes the gene that determines A, AB, B or O blood type.

They then divided participants into A, AB, B and O blood types. They compared the prevalence of those blood types in people with early stroke, late stroke and people who did not have a stroke.

Researchers found that people with early stroke were more likely to have blood type A and less likely to have blood type O compared to people with late stroke and people without stroke. Both early and late stroke were also more likely to have blood type B compared to controls.

When looking at people of European ancestry and comparing 5,825 people with early stroke to 29,320 people who did not have a stroke, the meta-analysis found that 48% of people with early stroke had blood type A compared to 45% of people with late stroke and 44% of people without stroke. They also found 35% of people with early stroke had blood type O compared to 39% of those with late stroke and 41% of people without stroke.

After adjusting for sex and other factors, researchers found those who had blood type A had a 16% higher risk of having an early stroke than people with other blood types. Those who had blood type O had a 12% lower risk of having a stroke than people with other blood types.

“This work deepens our understanding of early onset stroke development and changes,” said Jennifer Juhl Majersik, MD, MS, of the University of Utah and Fellow of the American Academy of Neurology, who wrote an editorial accompanying the study. “Future research is needed to help develop a more precise understanding of how stroke develops. This could lead to targeted preventative treatments for early onset stroke, which could result in less disability during people’s most productive years.”

A limitation of the study was the limited amount of diversity among participants, although 35% of the participants were of non-European ancestry.

The study was supported by the National Institutes of Health and Department of Veterans Affairs.