Tuesday, 3 March 2015

ClinicSpeak: sequencing DMTs, alemtuzumab after mitoxantrone

Time is brain. #ClinicSpeak #MSBlog #MSResearch

"The new buzz word in MS is sequencing of therapies. The study below is reassuring in that MSers with very active disease despite being treated with mitoxantrone responded to alemtuzumab. I have personally treated one such patient in the UK and he has done very well, in that he is NEDA. Unfortunately, prior to receiving mitoxantrone, and subsequently alemtuzumab, he had accumulated already accumulated severe disability (EDSS 7.0) and a lot of cognitive impairment. He has also subsequently become hypothyroid. This case and the study below reinforces the message that if you want to maximise the treatment benefits of alemtuzumab you need to use it as early as possible in the course of the disease."

"To maximise the benefits of highly effective treatments you need to use them early before you have acquire irreversible damage or lost brain and hence reserve capacity. Time is brain!"

Objective: Our study aimed to describe safety and neurological impact of alemtuzumab as last-line rescue therapy in MSers with aggressive MS, previously treated by Mitoxantrone (MITOX). 

Methods: Between June 2004 and October 2013, 13 MSers received alemtuzumab at 20 mg/day and 3 at 12 mg/day for 5 days. EDSS, relapses, secondary progression were prospectively assessed 12 and 6 months before treatment, at baseline and every 3 months. 

Results: Mean follow-up was 6.2 years [1-10]. Mean age at alemtuzumab start was 40 years [26-49] for 8 Secondary Progressive (SP) and 30 years [26-35] for 8 Relapsing-Remitting (RR) MSers. MS duration was 13.7 (±3) and 8.3 (±4) years, respectively. During the 12 months before alemtuzumab, annual relapse rate was 0.75 and 3.14, respectively and the 16 MSers accumulated 2-30 new gadolinium enhancing lesions. 4 MSers (suboptimal responders) received alemtuzumab during MITOX and 12 MSers 1-7.8 years after MITOX. Out of 8 SPMS, 2 were disease free up to last visit (4.7 and 8 years), 5 improved or stabilized but only transiently and 1 worsened. Out of 8 RRMS, 1 remained stable up to last visit (8.7 years) despite 1 relapse and active MRI at 18 months and 7 improved (1-4 point EDSS): 4 remained disease free up to last visit (12, 24, 38 months and 7 years), 2 were successfully retreated at 25 and 33 months and 1 worsened progressively 24 months after alemtuzumab. 2 MSers developed Grave's disease and 1 hypothyroidism. 

Conclusion: Alemtuzumab controls aggressive RRMS despite previous use of MITOX.

CoI: multiple

X rays and MS

Motamed MR, Fereshtehnejad SM, Abbasi M, Sanei M, Abbaslou M, Meysami S. X-ray radiation and the risk of multiple sclerosis: Do the site and dose of exposure matter? Med J Islam Repub Iran. 2014 Dec 9;28:145. eCollection 2014.

BACKGROUND:The sporadic cases of radiation-activated multiple sclerosis (MS) has been previously described, with a few studies focused on the relationship between radiation and the risk of MS. The aim of our study was to evaluate the association between history of X-ray radiation and MS.
METHODS:This case-control study was conducted on 150 individuals including 65 MS patients and 85 age- and sex-matched healthy controls enrolled using non-probability convenient sampling. Any history of previous Xray radiation consisted of job-related X-ray exposure, radiotherapy, radiographic evaluations including chest Xray, lumbosacral X-ray, skull X-ray, paranasal sinuses (PNS) X-ray, gastrointestinal (GI) series, foot X-ray and brain CT scanning were recorded and compared between two groups. Statistical analysis was performed using independent t test, Chi square and receiver operating characteristics (ROC) curve methods through SPSS software.
RESULTS: History of both diagnostic [OR=3.06 (95% CI: 1.32-7.06)] and therapeutic [OR=7.54 (95% CI: 1.5935.76) X-ray radiations were significantly higher among MS group. Mean number of skull X-rays [0.4 (SD=0.6) vs. 0.1 (SD=0.3), p=0.004] and brain CT scanning [0.9 (SD=0.8) vs. 0.5 (SD=0.7), p=0.005] was higher in MS group as well as mean of the cumulative X-ray radiation dosage [1.84 (SD=1.70) mSv vs. 1.11 (SD=1.54) mSv; p=0.008].
CONCLUSION: Our study was one of the first to show higher history of X-ray radiation in patients with MS compared to healthy controls. A possible association was also found between the dose and the site exposed to X-ray radiation and risk of developing MS.

One MSer recently asked is having radiation to the neck could influence MS lesions and they may be interested in this report that suggests that X ray may be risk factor for developing MS. again most of you will not have has an x-ray notably an skull X-ray.wonder

Cheaper Cardboard makes you happier

Najafi B, Ghaderi H, Jafari M, Najafi S, Ahmad Kiadaliri A. Cost Effectiveness Analysis of Avonex and CinnoVex in Relapsing Remitting MS. Glob J Health Sci. 2014 Oct 9;7(2):38659. doi: 10.5539/gjhs.v7n2p139.

INTRODUCTION:Multiple sclerosis is a chronic and degenerative neurological disease characterized by loss of myelin sheath of some neurons in brain and spinal cord. It is associated with high economic burden due to premature deaths and high occurrence of disabilities. The aim of the current study was to determine cost effectiveness of two major products of interferon 1a in patients with relapsing-remitting multiple sclerosis.
METHOD AND MATERIALS: Altogether, 140 patients who have consumed Avonex and CinnoVex in Relapsing Remitting MS for at least two years were randomly selected (70 patients in each group). Health-related quality of life (HRQoL) was assessed using the adopted MSQoL-54 instrument. Costs were measured and valued from Ministry of Health and Medical Education (MOHME) perspective. Two-way sensitivity analysis was used to check robustness of the results.
RESULTS: Patients in CinnoVex group reported significantly higher scores in both physical (69.5 vs. 50.9, P<0.001) and mental (63.3 vs. 56.6, P=0.03) aspects of HRQoL than Avonex group. On the other hand, annual cost of CinnoVex and Avonex were 2410 US$ and 4515US$ per patient, respectively (P<0.001).
CONCLUSIONS: The results showed that CinnoVex was dominant option over the study period. It is suggested that results of the current study should be considered in allocating resources to MS treatments in Iran. Of course, our findings should be interpreted with caution duo to short term horizon and lack of HRQoL scores at baseline (before the intervention)
CinnoVex became the first biogeneric clone of interferon-beta to be used for treatment of MS, when it was approved by the Iranian Food and Drug Administration. Based on quality of Life scores MSers using CinnoVex appeared to be happier than people using Avonex for the USA. Is this because people were not using American product or the fact that it was 20 times cheaper. Is it twenty times better...I doubt it, but they are not all created equal.

If you have a limited budget do you want to fleeced by the the more expensive alternative? 

Many people prefer to get their drugs from the brand they trust. This is a product of Marketing. Just as you can pay for the packaging of brand leaders or supermarket generics, which are 10 times cheaper, even when beta intererons are made in essentially the same place...people can be convinced to pay more for the cardboard.

Breathing problems in MS - the unseen entity

Respir Med. 2015 Feb 12. pii: S0954-6111(15)00021-9. doi: 10.1016/j.rmed.2015.01.018. [Epub ahead of print]

Respiratory dysfunction in multiple sclerosis.



Respiratory dysfunction frequently occurs in patients with advanced multiple sclerosis (MS), and may manifest as acute or chronic respiratory failure, disordered control of breathing, respiratory muscle weakness, sleep disordered breathing, or neurogenic pulmonary edema. The underlying pathophysiology is related to demyelinating plaques involving the brain stem or spinal cord. Respiratory complications such as aspiration, lung infections and respiratory failure are typically seen in patients with long-standing MS. Acute respiratory failure is uncommon and due to newly appearing demyelinating plaques extensively involving areas of the brain stem or spinal cord. Early recognition of MS patients at risk for respiratory complications allows for the timely implementation of care and measures to decrease disease associated morbidity and mortality.

Full-size image (42 K)
An MS plaque (arrows) in the medulla, the breathing center of the brain can lead to acute breathing difficulties

We don't routinely assess for breathing difficulties in our patients during their OPD visits. The things we do check for are relapses, walking problems, cognitive difficulties, bowel/bladder dysfunction, including urinary tract infections. This may lead most to believe that it doesn't exist or is not serious. If anything, the opposite is true. 

In general breathing problems occur in MSers with advanced stage of disease. It is thankfully rare in ambulatory/walking MSers. Rarly, it occurs acutely in RRMS, caused by MS plaques in the cervical cord or medulla (see above picture).

Over the past year, I looked after two MSers with breathing difficulties, both heavily disabled (EDSS 8.5-9.0), but requiring in-patient care primarily because of their breathing. First MSer would go silent mid conversation, turning blue around the lips - after momentary panic our initial thoughts were that it was a seizure, but his O2 probe showed that his SATS (O2 saturation) had dropped to 40% - this was Cheyne-Stokes breathing. Second MSer in fact had epilepsy but worsening seizure control due to recurrent aspiration pneumonia (chest infections resulting from breathing in secretions from the mouth or stomach into the lungs). 

It is therefore not surprising that breathing problems account for 47% of all deaths in MS. The standardized mortality ratio is 2.79 (95% CI 2.44 - 3.18) i.e. almost three times more likely die prematurely due to breathing difficulties.

It is therefore critical to recognize those at greater risk and initiate appropriate measures in a timely manner. Pointers to potential breathing problems:
  • a weak cough
  • swallowing difficulties
  • difficulty controlling breathing
  • shortness of breath and excessive daytime sleepiness 
  • shortness of breath on lying flat
  • sleep disordered breathing (obstructive/central sleep apnoea)
The above can be worsened by MS-related fatigue, drugs or nerve conduction block due to elevated body temperature. 

And general considerations in management include:
  • prompt treatment of chest infections
  • influenza and streptococcal pneumonia vaccinations
  • smoking cessation
  • avoidance of sedatives

Specific measures include:
    • chest physiotherapy and cough assist devices in those with a weak cough
    • non-invasive ventilation for acute failure in breathing or those with nocturnal sleep difficulties for long-term support of symptoms
    • targeted respiratory muscle training exercises to boost strength and endurance (can be administered over 4-12 weeks)