A Brief History of Stroke

Stroke is a leading global cause of death and disability-adjusted life years (DALYs, see below for definition), second only to ischemic heart disease. The incidence of stroke varies across different countries and increases exponentially with age. 

First defined as ‘apoplexy’ by the father of medicine Hippocrates himself in 2400BC, it was not until around the 1600’s that the link between the potentially devastating sudden symptoms and the brain was made (hence the name ‘apoplexy’, which meant in Greek ‘struck down by sudden violence’). This discovery was made by the documentation of intracranial haemorrhage in the brains of cadavers who died of stroke by Johannes Wepfer (Since 2005 the “Johann Jacob Wepfer Award” is given at the European Stroke Conference for outstanding work in cerebrovascular diseases). 

After extensive work in defining the anatomy of the cerebral vasculature by Thomas Willis in Oxford 1664, and the discovery of an anatomo-pathological association by the Paris Medical School in the late 1800s, apoplexy became better known as ‘cerebrovascular accident’.  The term ‘stroke’ was a lay term, originating from the belief the disease was a sort of ‘stroke of gods hand’ or ‘stroke of justice’, a punishment for wrongdoing or pleasure-seeking. It later became the definitive name for the disease in 1962 when the chest and heart association produced a booklet titled ‘Modern Views on ‘Stroke’ Illness’.

Even at this time, the mid twentieth century, it seemed doctors still approached stroke with slight nihilism or hopelessness. Up until 1935 bloodletting was the primary therapy for stroke. Vomits, purges and enemas were all treatments for stroke in the beginning of the nineteenth century, not so different from Hippocrates own ‘replacement of humours’ before the start of the millennium. Nothing seemed to improve the prognosis, patients miraculously recovered, died or faded away with permanent disability; modern medicine had a long way to go still!

Bloodletting, 'back in the day'

In the 1950s doctors began to experiment with angiography, anticoagulants and surgery for the treatment of stroke. A few years later, team approaches to stroke patients started in many hospitals with the collaboration of physiotherapists, nurses, dietitians, surgeons, internists, occupational therapists, speech therapists and general practitioners. Rehabilitation became one of the main contemporary treatment responses to stroke. By the end of the 20^th century and with birth of stroke associations around the world, there seemed to be some light in the tunnel, perhaps stroke is curable and preventable. 

Stroke treatment and management has come a long way in the last fifty years, advancements in angiography and the introduction of aspirin therapy and intravenous thrombolysis have improved survival massively. 

In 2008, stroke moved from being the 3^rd leading cause of death in the USA to the fourth, it then jumped a further rank to fifth in 2013, a reflection of accelerating science and improving prognosis!

DALY: The sum of years of potential life lost due to premature mortality and the years of productive life lost due to disability. One DALY can be thought of as one lost year of "healthy" life. The sum of these DALYs across the population, or the burden of disease, can be thought of as a measurement of the gap between current health status and an ideal health situation where the entire population lives to an advanced age, free of disease and disability.

References:

-http://vizhub.healthdata.org/gbd-compare/ Institute for health metrics and evaluation. Accessed 03/04/2017. Images.

-Catherine E. Storey, Hans Pols, Chapter 27 A history of cerebrovascular disease, In: Michael J. Aminoff, François Boller and Dick F. Swaab, Editor(s), Handbook of Clinical Neurology, Elsevier, 2009, Volume 95, Pages 401-415, ISSN 0072-9752, ISBN 9780444520098, http://dx.doi.org/10.1016/S0072-9752(08)02127-1.

 -Molnár Z. Thomas Willis (1621-1675), the founder of clinical neuroscience. Nat Rev Neurosci. 2004;5(4):329-35.

-Van der worp HB, Van gijn J. Clinical practice. Acute ischemic stroke. N Engl J Med. 2007;357(6):572-9.

-Pound P, Bury M, Ebrahim S. From apoplexy to stroke. Age Ageing. 1997;26(5):331-7.

Pancreas Transplantation BMJ State-of-the-Art Review Summary

(Another medical student orientated summary of a recent review, this time Pancreas Transplantation.)
Successful pancreas transplantation can result in durable glycemic control and improved survival for patients with diabetes. There seems to be no other treatment in medicine that has the same improving success rates over time and is being applied less and less (the number of pancreas transplants performed in the US has decreased every year during the past decade). In other words, more patients could probably benefit from pancreas transplantation than currently undergo the procedure. 

Most people are diagnosed with type 2 diabetes, with type 1 diabetes accounting for 8-10% of all diabetes cases.
In the UK 3.5 million people are diagnosed with diabetes, with approximately 0.5 million still to be diagnosed. The incidence is increasing.

First successful pancreas transplant was in 1966, at the University of Minnesota.
The number of transplants increased steadily until 1996.
Survival at this point (1996) was 91% at one year and 84% at three years.
The introduction of ciclosporin in the 1980s dramatically increased survival, further efficacy of transplant was enhanced with introduction of tacrolimus and mycophenolate in the 1990s.

Between 2005 and 2014 pancreas transplantation number decreased by 20%. Reasons for this decline were probably; improved medical management of diabetes, decline in organ donor quality (more obese and old), lack of consistent referral of transplant candidates from endocrinologists.

Three main pancreas transplantation types:

• PAK = pancreas after kidney transplant (the main role of this type is avoid the morbidity and mortality asociated with dialysis therapy; patients with type 1 diabetes have at least a 33% mortality in teh first five years after starting dialysis). 
• PTA = pancreas transplantation alone (has higher rates of technical graft loss and acute cellular rejection, however a very small number of this type are performed, no no reports have rigorously studied the efficacy or quality of life benefits)
• SPK = simultaneous pancreas kidney transplant (most common type of pancreas transplant, typically both organs from the same donor)

Success rates of pancreas transplantation have improved with time likely due to increasing experience with these complex patients.

UK current survival rates SPK five year survival 88%, Pancreas only transplants five year survival 78%.

No real studies have directly compared the costs of pancreas transplant vs conventional medical therapy but there have been theoretical models that concluded that SPK is the most cost effective strategy after accounting for varying probabilities of patient and graft survival.

• To date there have been no randomised controlled trials comparing the different forms of pancreas transplantation against for example intensive insulin therapy, islet transplantation. 
• However many single centre studies and registry analyses suggest that pancreas transplantation provides a net benefit compared to kidney transplant alone for patients with both diabetes and chronic kidney disease. 
• More controversial is the impact of pancreas transplantation on patient survival in patients with diabetes and preserved renal function. One analysis of transplant registry data reported a survival disadvantage for PAK and PTA recipients. 

Because pancreas transplantation can also establish normoglycemia it is reasonable to infer that this intervention would also improve or stabilise end organ complications (eg. retinopathy, nephropathy).

Complications:
Diabetic nephropathy (a microvascalur complication of diabetes) is one of the most important complications of diabetes.
Single centre studies with small cohorts have suggested that pancreas transplantation has a beneficial effect on secondary complications of diabetes.
Data is limited on the long term complications, have been reports of increased infections and hematologic cancers after transplantation.

Quality of life:
QoL improved rapidly after transplantation (measured at four months), the effect did however flatten out later. A minority had decreased QoL emphasising the importance of pre-transplant education to establish realistic expectations for the patient.

Clinical trials:
No multicentre trial has been designed to truly evaluate the true efficacy of transplant compared to best medical therapy in type 1 diabetes.

Islet transplantation (ITA):
ITA is less invasive.
Has good short term results but five year insulin Independence rate are around 11%, despite this these patients achieved avoidance of hypoglycemia and near normal glucose control.
Comparison of ITA vs PTA; PTA has higher morbidity, authors of mentioned study concluded that ITA produces similar outcomes to PTA.

Artificial pancreas:
A closed loop system with a subcutaneous sensor that transmits glucose measurements to an external insulin pump that deliver insulin subcutaneously when needed.
Addition of glucagon in the future could prevent hypoglycemia.
The use of such devices requires the patient reaches a certain level of understanding.
Results from international diabetes closed-loop trial conducted on real patients will be out in 2019.

Future directions:

"Pancreas transplantation stands at a crossroads—without a systematic approach to the procedure and its outcomes, transplant volumes, especially those for PTA and PAK, may continue to decline and the procedure take second stage to therapies such as islet transplantation and closed loop insulin and glucagon delivery systems..... a more systematic approach to characterizing the successes and limitations of pancreas transplantation is needed."

Need to develop a uniform definition of graft failure. The most common definition of graft failure at the moment is the requirement of exogenous insulin therapy.
Need the development of biomarkers to diagnose rejection and monitor patient immune status.

UK guidelines:

In the UK, patients with the following conditions are considered for pancreas transplantation135: 

•  Pancreas transplantation alone or islet transplantation alone: patients with severe hypoglycemic unawareness but normal or near normal renal function

•  Simultaneous pancreas and kidney transplantation or simultaneous islet and kidney transplantation: patients with renal failure and insulin dependent diabetes 

•  Pancreas after kidney transplantation or islet after kidney transplantation: patients with functioning kidney transplants and diabetes. Most patients who are considered have type 1 diabetes but some patients with insulin dependent type 2 diabetes may also be suitable candidates.

This summary was for the following paper: http://www.bmj.com/content/357/bmj.j1321
(all the information and images were from the above paper).

NEJM Maternal Immunization Review 2017 Summary

(A medical student orientated summary of a recent NEJM review)
Most childhood vaccines do not start providing adequate protection until the infant is several months old. The immunity gap between birth and this time can be addressed by maternal immunization.

Sex hormones modify immune responses:

• Increase in estradiol is associated with increased Th2 responses and reduced Th1 immune responses.
• Increased progesterone levels is associated with reduced immune response in general
• Overall phagocytic responses, alpha-defensin expression, neutrophil, monocyte and dendritic cell numbers may be increased in 2nd and 3rd trimester in general during preganacy. 
• (may explain suboptimal responses to viral infections such as influenza in pregnancy)
• pregnancy is not a generalised state of immunosuppression.

Evidence regarding the immunogenicity of vaccines administrated  during pregnancy is mixed

Current recommendations are for pregnant women to have influenza and Tdap (tetanus-diphtheria-acellular pertussis) maternal immunisations

Influenza vaccine:

• Few low income countries regularly vaccinate pregnant women against influenza
• A substantial burden of illness among pregnant women is attributable to seasonal influenza
• The efficacy within infants after birth ranged from 30% to 63% (good for mom, ok for baby)
• There may be potential for protection against adverse birth outcomes, two studies detected a difference in low birth weight however the others did not. One study was sufficicnetly powered to detect a difference but the promising result was offset perhaps by the overall low baseline birth weight. So perhaps the vaccine is more useful as a protection against adverse outcomes. 
• influenza infection is associated with  an increased rate of subsequent bacterial infection particularly pneumococcal disease. (in fact a substantial proportion of deaths during the 1918 flu epidemic were probably due to strep.pneumoniae). 
• use of maternal vaccine and infant vaccine together showed better results than infant vaccine alone in prevention of respiratory illnesses with fever and medically attended acute respiratory illnesses. 

Pertussis vaccine:

• Young infants have a disproportionately high burden of severe pertussis in the population.
• studies on the pertussis vaccine have shown high effectiveness and a reassuring safety profile (there were no increaes in adverse birth or pregnancy outcomes). 
• There was a slightly higher rate of chorioamnionitis but the authors explained this as perhaps due to practice of labelling fevers as chorioamnionitis to protect from litigation in the USA where the study was conducted
• There is concern though that the vaccine may reduce the immungenicity of the infant DTP (diphtheria-tetanus-pertussis) vaccine. With studies suggesting this, however the clinical relevance is uncertain. 

Maternal vaccines in development include vaccines against RSV (respiratory syncytial virus) and GBS (group B streptococcus).

RSV vaccine:

• RSV is the leading cause of viral acute lower respiratory tract illness and the highest morbidity is among preterm infants. Most deaths due to RSV occur in infants
• 2-3% of all neonatal deaths are attributable to RSV.
• Vaccine is needed due to the high burden of RSV infection, particularly among young infants.
• Several RSV vaccines are in development, targeting the RSV F and G proteins mainly. 
• Given that preterm infants are a high risk group, recommendation for the gestational age of vaccination will have to take into account adequate antibody transfer for preterm infants. 
• In the 1960s a formalin inactivated form of the vaccine against RSV for children was researched. It led to an 'enhanced RSV disease', and increased rates and severity of RSV lower respiratory illness. Thought now to be due to a lack of protective antibodies being produced with an increase in CD4+ priming in the absence of CD8+ cells. This abherrent vaccine slowed further research into RSV vaccines.
• The benefit of a maternal vaccination is that it would bypass immunologic events that would lead to an enhanced RSV disease in infants. 

Group B strep vaccine:

• Early onset GBS infection occurs in neonates younger than 7 days and is characterised by sepsis without a focus, pneumonia or meningitis.
• Late onset GBS infection occurs in infants who are 7 to 89 days of age and is characterised with higher rates of meningitis.
• Invasive GBS infection in pregnant women is associated with stillbirth
• GBS is transmitted from colonised mothers during birth (hence why there is universal maternal screening with intrapartum antibiotic prophylaxis).
• One in five pregnant women have evidence of GBS rectal or vaginal colonisation at 23-26 weeks. 
• Screening with prophylaxis programmes mentioned above have resulted in reductions in early-onset GBS disease but NO reduction in late onset disease. 
• A maternal GBS vaccine could help reduce the burden of GBS disease, particularly late-onset disease in infants. 
• there is a trivalent vaccine in development that covers serotypes Ia, Ib and III. The global disease burden includes serotypes II and V, therefore a vaccine will need to be developed still to cover against also these subtypes

Incorporating maternal vaccines into antenatal care has been a challenge in many locations, with the maternal influenza vaccination rate in the US estimated to be around 50%.

Link to paper: http://www.nejm.org/doi/full/10.1056/NEJMra1509044

(all the points above and images were taken from the paper linked above)