ST. JMC JOURNAL OF MEDICINE ISSN 0970-4221 VOL.III NO. 2 JUNE 1990
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ISSN 0970 - 4221
ST. JOHN'S MEDICAL COLLEGE
JOURNAL OF MEDICINE
VOL III No 2
June 1990
EDITORIAL
31
CARDIOLOGY SYMPOSIUM - RHEUMATIC FEVER
Foreword '
33
Rheumatic Fever - Pathogenesis, Prevalence, Distribution, Frequency
34
Manifestations, Diagnosis, Treatment and Prevention of Rheumatic Fever
36
Surgery for Rheumatic Valvular Disease
42
ORIGINAL ARTICLE
Vertical versus Horizontal immunisation among tribal communities
46
REVIEWS
Neurological disease with a presumed immune aetiology
48
Therapeutic advances in Parkinson's disease
53
CLINICAL PRACTICE
The Peak Expiratory Flow Rate
57
ADVANCES IN TECHNIQUE
Laryngeal Mask
59
INFORMATION FOR CONTRIBUTORS
EDITOR-IN-CHIEF
Ashley. J. D'Cruz
Submitting the Manuscript
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REFERENCES
PUBLISHER
Prof. A.F.A. Mascarenhas
Principal
References should be compiled at the end of the articles according to the order of citation in the text,
not alphabetically. They should be typewritten, double-spaced under the heading REFERENCES.
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EXAMPLES OF REFERENCES
Journal Articles upto six authors, list all names:
Kurpad AV, Shetty PS: Dietary Fibre and the colon. StJohn's J Med, 1988;1.5-12.
Journal Articles more than six authors, list three authors followed by et al:
Complete book
Gallagher JR: Medical Care of the Adolescent (ed 2). New York, Appleton, 1966; pp 208-215
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St.
John’s
Medical
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==
EDITORIAL
MODERN CLINICAL BRACHYTHERAPY
The speciality of brachytherapy occupies the pride of place of modern radiptherapy and has evolved rapidly since its
inception in 1896. Radio therapy implies the delivery of ionising radiations to malignant tissues to tumoricidal doses and is
a very common mode of therapy in the treatment of malignant disease. Most often, these radiations are delivered from a
distance as in a cobalt-60 machine and is called tele-radiotherapy. The less common form of radiotherapy is by injecting
radio-nuclides systemically as in the case of thyroid tumors with lodine-131. Of late, the third form of radiotherapy,
Brachytherapy, has captured a great amount of interest in the quest of conquering cancer.
Brachytherapy utilizes encapsulated radionuclides placed within a tumour or in close proximity to tumour in order to deliver
cancericidal dosages of radiation. The term derives from the Greek ‘brachy’ for short. Its history began in Paris in 1896, soon
after the discovery of X-rays by Roentgen, when Henri Becquerel observed the darkening of a photographic plate by
uranium crystals. Two years later, Marie and Pierre Curie isolated a new radioactive substance - radium - from pitchblende.
Very soon radium was utilisedforthetreatmentof various forms of cancer. In 1934, Irene Curie and Frederic Joliot discovered
the process of artificial radioactivity creating a revolution in brachytherapy. This meant that radionuclides other than radium
could now be used in cancer treatment. In 1953, Henschke devised a system by which radiation hazards to operating technical
staff - doctors, nurses and technicians could be reduced to a minimum. This "afterloading" system set the trend for the present
day brachytherapy practice. A set of rules defining how best an arrangement of radioactive sources could be placed in and
around a tumour were defined by a British group of radiotherapists as early as 19341 and later by the French group in the
1960s.2
Clinical brachytherapy can bedivided into 3 arms: Interstitial, Intracavitary/lntralumenal, Surface/mould systems. In interstitial
brachytherapy, radioactive sources are placed within a tumour mass while in intracavitary and intralumenal brachytherapy
these sources are placed in natural body cavities to deliver tumoricidal doses. In surface/mould systems, the sources are
placed in an individualised mould which in turn is placed over a superficial tumour.
Radium was a very popular and a widely used brachytherapy source until the discovery of cobalt - 60 radioactive sources. Its
radio-protection problems, very long half-life, gaseous daughter product etc. necessitated its replacement with radionuclides
like Cobalt-60, Caesium-137, lridium-192, Strontium/Yttrium-90, etc. Also, in the radium era, sources were manually
introduced into tumour from the beginning of a procedure: "preloaded system". By 1954, after loading systems, in which source
conduits were placed in tumour into the radioactive systems were placed at the very last moment after verification of its
disposition and geometry, very greatly reduced the hazards of the preloaded era. These afterioaded systems were either
manual or remotely operated and ensured almost absolute radio-protection without any compromise on tumour kill.
Intracavitary and interstitial brachytherapy have numerous clinical indications. The former utilises Caesium-137 or Cobalt-60
sources, whereas the latter employs lridium-192 predominantly. Surface moulds are relatively uncommon and these utilise
either Cobalt-60 or Caesium-137 sources.
Gynaecologic Oncology radiotherapy forms the bulk of intracavitary brachytherapy. Patients with carcinoma uterine cervix,
body uterus and vagina undergo this procedure during their treatment. The procedure entails introduction of source carriers
into the uterine cavity and vaginal fornices (as ovoids) appropriately, and subsequently loading these with radioactive
sources. In advanced stages, these patients undergo brachytherapy after initial radiotherapy, in early stages brachytherapy
can be delivered as a single therapy option. The dose prescribed is based on the classical Manchester system relating to
point ’A’ and 'B', but in recent years, the International Commission on Radiation Units have suggested an alternative
system3.
Intralumenal brachytherapy is the irradiation of malignancies of hollow organs such as oesophagus, bronchus, biliary tree etc.
As there possibly could be practical problems in keeping these source systems in situ for longer periods of time, higher
activities of radioactive material are used (high dose rate systems) thereby effectively reducing treatment time.
Interstitial brachytherapy forms the mainstay of radiotherapy management in early head and neck cancer. Here, the tumour
volume is implanted with hollow steel needles which are substituted by plastic tubes which will eventually house within it the
radioactive source. There are many variants in this technique, but the ’Plastic tube' technique is very popular.
St. John’s Medical College Journal of Medicine
In head and neck cancer, interstital brachytherapy is indicated in various clinical situations. In very small lesions (e.g. T1 lesion
of buccal mucosa), it can be employed as the primary treatment mode. In larger or extensive tumours, it is used as a boost
therapy after initial teletherapy which reduces the tumour significantly. In recurrent primary tumours or nodal disease after
previous therapy, when therapeutic options are limited, interstitial brachytherapy can be attempted for possible control,
delivering very low dose rate protracted treatments to minimize damage to normal tissues.4
Interstitial brachytherapy is also indicated in various other areas like skin tumours, prostrate rectal tumours, breast cancer
etc. In all its indications, interstitial systems utilize various methods in dose specification like the Manchester system and the
Paris system.
Surface moulds are used in certain areas where the lesion is very superficial and where underlying bone or cartilage prevents
a satisfactory interstitial implant to be performed. Some clinical examples are, tumours of the scalp, pinna, chest wall, etc.
As the dose intensity is maximum at the tumour centre but falls off rapidly away from it, the underlying normal tissues are fully
spared.
Brachytherapy has made good progress over the years towards optimal and comprehensive cancer radiotherapy. The
introduction of Californium-292 has added a new perspective and the use of interstitial hyperthermia has tremendously
improved the outcome for patients with recurrent disease.
The main thrust of modern brachytherapy is towards conserving tissue at the same time delivering tumouricidal doses to
malignant tissues. It has emerged as a curative modality in the gamut of current oncology management. This is due to the
development of better radionuclides, new and safe afterloading techniques and better dosimetry with the use of computers,
obtaining the unique advantage of delivering maximal doses to the tumour without damaging normal structures.
M. Udaya Kumar MD,DNB(RT),DCCF(Paris).
I
Lecturer in Radiotherapy
Kidwai Memorial Institute of Oncology
Bangalore 560 029.
References:
1.
Meredith WJ: Radium Dosage, E&S Livingstone Ltd., 1967
2.
Pierquin B, Dutreix A, Paine CH et al: The Paris System in Interstitial radiation therapy, Acta Radiol Oncol. 1978;17:33-37.
3. International Commission on Radiological Units and Measurements. Dose and volume specifications for reporting intracavitary therapy. ICRU, Report 38,
Betheseda, Md., 1984.
4.
Gerbaulet A, Udaya Kumar M : Current brachytherapy practice in head and neck cancers; La Mededne en France. 1989;37:247-254.
32
VOL III No. 2----
St. John’s Medical College Journal of Medicine
CARDIOLOGY SYMPOSIUM - RHEUMATIC FEVER
FOREWORD
RHEUMATIC HEART DISEASE
(WHAT PRICE? - SORE THROAT I)
Rheumatic fever and
including ours.
rheumatic heart disease are still
major problems in developing countries,
While the West and USSR have more or less eliminated rheumatic fever and its crippling sequelae
rheumatic heart disease, a huge burden is placed on our medical resources in the treatment of these
patients many of whom may require open heart surgery, apart from the socio - economic effects on
the afflicted and their kith and kin.
It is estimated that about 6-12 per thousand children of school going age are affected with rheumatic
heart disease. Moreover much younger children suffer from the so-called Juvenile mitral stenosis with
its unrelenting progression. It is also a specialised problem when women of child bearing age are
affected and more so in pregnancy which can create requirement of emergency care including surgery
in some instances.
While in suitable cases, closed mitral valvotomy or even valvuloplasty can be offered, many will
require open heart surgery for valve replacement/repair. This can be single or multiple valve
replacement. While the mitral valve bears the brunt other valves can also be affected in addition. The
problem of anticoagulation therapy after replacement with prosthetic valve looms large in our country,
especially in the pregnant woman.
Amongst surgery for acquired heart disease, rheumatic heart disease still takes a major chunk in our
country, though coronary artery disease is also increasing in alarming proportions.
We have to emphasise on the preventive aspects or else pay a heavy price for ‘sore - throat’.
This symposium, hence, is topical. The epidemiological aspects, the pathogenesis, and the clinical
features, the management including the surgical aspects and the advent of valvuloplasty are well
covered by the respective authors concerned. I am sure this number will draw a lot of careful attention
by the readers. I have great pleasure in writing this foreword to the symposium.
Lt. Gen. G.R. Narayanan m.d., d.m., facc, fiams.
Emeritus, Professor - Dept, of Cardiology
St. John's Medical College & Hospital
Bangalore - 560 034.
JUNE 1990
33 —
CARDIOLOGY - SYMPOSIUM
St. John's Medical College Journal of Medicine
RHEUMATIC FEVER
PATHOGENESIS, PREVALENCE, DISTRIBUTION, FREQUENCY
P.R. NAYAK
Rheumatic heart disease continues to be the major cause
of cardio-vascular death in developing countries. There has
been no major change in the prevalence of acute rheumatic
fever (RF) orthe incidence of rheumatic heart disease (RHD)
in the country since its problem was initially noticed by Scott
in 1938. In the West the incidence of RF and RHD has fallen
dramatically and except for isolated outbreaks the reported
cases have been few and far between.
PATHOGENESIS
In the Fifties and Sixties, there was an intense debate as to
whether group A Beta-Haemolytic Streptococci (GABHS)
caused rheumatic fever and what unique properties made
certain strains of GABHS Rheumatogenic and others not.
Further, interesting questions were raised as to why only
a small percentage (3-4%) of those infected by GABHS
developed rheumatic fever.
The evidence put forward to support the theory that GABHS
causes Rheumatic fever has been clinical, epidemiological,
immunological and prophylactic evidence to show the link
between GABHS and rheumatic fever. However, these
evidences are not conclusive.
Rheumatogenic Streptococci - It appears that certain
properties have to be fulfilled by the GABHS to be
rheumatogenic.
1.
The infection must be localised to the throat and not to
the skin or other sites.
2.
The organism’s virulence must be high to produce RF
(this is supported by the fact that patients with higher ASO
titre in epidemics have greater incidence of RF as compared
to those with low ASO titres).
3.
The virulence seems to be determined by the ‘M
Protein’ which
is
associated with resistance to
phagocytosis by precipitating fibrinogen from human blood
on the surface of the streptococci, thus blocking the
interaction of the streptococcus with complement and
preventing recognition by leucocytes. The M types also keep
changing with each epidemic thus increasing the problem of
vaccine development. GABHS with any strain ‘M’ protein
localised to the throat are potentially rheumatogenic. The
host factors that come into play when a patient develops
rheumatic fever are:
DR.P.R.NAYAK M.D., D.M.
DEPARTMENT OF CARDIOLOGY
STJOHN'S MEDICAL COLLEGE & HOSPITAL
BANGALORE - 560 034
— 34
i)
Age : Rheumatic fever incidence is highest in the age
group of 5-15 years, though other ages may be susceptible
and the incidence keeps decreasing with age. First attacks of
rheumatic fever are almost unheard of after the age of 40
years.
ii)
Environmental : People living in crowded
and
unhygenic conditions have a much higher incidence of
Rheumatic fever. No race is exempt. It has been noticed that
with improvement in living standards, housing, education,
the incidence of
rheumatic fever falls drastically as
demonstrated by the western nations.
iii) Acquired susceptibility - A past history of rheumatic
fever increases the likelihood of recurrence, and this
decreases with the passage of time and is as high as 50% in
the first year. It then levels off to around 10% and stays at
that level after 5-10 years.
iv) Genetic factors: Thus far no definite genetic link has
been established, but it has been shown in studies by Ayoub
et al, that while RF patients had an increased frequency of
HLA-DR4 and black patients increased frequency of DR2. An
increased incidence of B cell allotype cell antigen in patients
withRF has also been demonstrated, the exact significance
of this finding is not known.
An interaction of host factors, presence of a virulent form of
GABHS with ‘M* protein which causes a pharyngeal infection
appear to be the important prerequistes for the development
of RF. The pathogenetic mechanism by which the above
variables induce Rheumatic fever is not confirmed. The
theories are:
1.
2.
Role of Toxins
Immunologic - Autoimmunity
Cross Reactive Antibodies.
These theories are not established as the only mechanisms
for the occurence of rheumatic fever.
PATHOLOGY
Classically stated, rheumatic fever “Licks the jointsand kicks
the heart”. The pathological manifestations of acute
rheumatic fever are manifested in the cardiac and extra
cardiac tissues, but the long term sequalae are manifested
only in the heart.
Pathologically the classical lesion described in RF is the
“Aschoff nodules” which is a form of fibrinoid necrosis.
EPIDEMIOLOGICAL DATA
This part of the article will attempt to summarize the available
literature on rheumatic fever in the country. There have been
several systematic attempts to define the extent of the
VOL Ill No. 2—
St.
John’s
Medical
College
Journal
of Medicine
problem in the country, the important sources of information
are:
1.
2.
3.
4.
Several studies conducted by institutes and the ICMR.
Births and deaths registry
Employees State Insurance Corporation statistics
School surveys
The data from the above sources is not uniform in the method
of collection and classification. This to an extent has, vitiate
the figures.
The important surveys carried out are the following
1. Collaborative study on prevalence of RHD in schools
was carried out between 1972-75 at Agra, Delhi, Bombay,
Hyderabad andAllepey. The prevalence rates varied from
the low of 1.8\1000 children in Bombay to the high of
11.1X1000 at Delhi, no definite conclusions could be drawn
about this wide regional difference. Some of the other
interpreted data in this study was that the prevalence was
higer in government and corporation schools, and in childern
with poor nutritional status. History of RF was obtained in
2.5 to 3.5% of the childern, RF prevalence varied from 0.05
to 1.7\1000 screened population. The commonest cardiac
lesion was mitral regurgitation, followed by mitral
regurgitation stenosis, and isolated mitral stenosis.
2. A survey carried out in Delhi in the period of 1982-83,
showed a prevalence of RHD of 9.07\1000, thus showing that
there was no reduction in the prevalence as compared to the
earlier period of 1972-75.
3. The only systematic attempt of screening of the
population was made in Chandigarh by Berry from the Post
Graduate Institute of Medical Sciences. The following data
was obtained from the nearly 35,000 cases screened. The
overall prevalence of RHD was 1.62X1000, and the male
female distribution was 1.23X1000 and 2.07\1000 population
screened. 62% ofthe patients had a past history suggestive
ofRF. The mitral valve was involved in 100% of the women
and 85% of the men, whereas the aortic valve involvement
was higher in men (42%) as compared to women (14%).
4. The studies from Vellore on Hospital based patients
have shown that about 40% of all cardiac admisssions are
due to rheumatic heart disease and constitute 36.5% of
cardiac deaths.
The valvular involvement shows mitral valve alone involved
in 56% of the patients, aortic valve in 13.2%, mitral and aortic
valves in 17.8% and mitral, aortic, tricuspid in 11.7% of the
cases. Males constituted 51% of the patients. The mean
age of the first attack of RF was 10.9 years as
inferred
from history. History of Arthralgia was obtained in 56.5%,
polyarthritis in 45%. 71.2% of the patients belonged to the
low socio-economic group.
As regards RF, of the 1,120 patients analysed, sex wise
there was a male preponderance (57.17%). The age of
presentation varied from 5 to greater than 30 years. Carditis
JUNE 1990
was the most common form of presentation (81.6%),
Polyarthralgia 50%, Arthritis 36%, chorea 3%, nodules 5%.
None of the cases were observed to have erythema
marginatum. A raised sedimentation rate was seen in 93.6%
and elevated ASO titres in 73% of the cases.
5. The Employees State Corporation Data survey of
employees and their families showed a very high rate of
incidence of Rheumatic fever. (5.1X1000 employees and
4.7X1000 for families and the prevalence of RHD to be
0. 7X1000 employees and 1.1X1000 families).
This available data suggests that RF is a major problem in
our country with an incidence of about 100-120X1000000
population
as compared to 1-5X100,000 in
western
populations. The studies
have
also shown that the
prevalence is much higher in the lower socio-economic
strata. Earliest attacks have been reported at the age of
three years. Normally attacks prevail between 5-15years.
The incidence does decrease after the age of 20 years, but
a significant percentage of the patients still present with RF
in the fourth decade as exemplified by the figures from
Vellore.
The manifestation of RF as analyzed from the Vellore and
Rheumatic Fever Criteria Study show no difference from
the western studies and carditis and polyarthritis form the
major modes of presentation, arthalgia is also seen but
usually in patients with pre existing RHD. Subcutaneous
nodules and chorea are rarer manifestations, and erythema
marginatum is rarely ever seen.
The distribution of valve lesions in RHD show that mitral
regurgitation is the commonest lesion followed by mitral
stenosis, isolated aortic regurgitation is rare (higher
incidence in Vellore series probably due to it being a reference
centre).
One note of caution is that there is a common teaching that
the Jones criteria are not applicable to Indian conditions. But
hard data does not corrobrate this. Well taken histories and
systematic studies have shown that the criteria are as much
applicable to Indian conditions as they are in the west.
In summary, the problem of Rheumatic fever continues to
plague the Indian sub continent and will place a heavy load
on the finances and time of the health community. A long
term and objective policy is required by the Government to
bring down the incidence of this dreaded disease. Steps
taken now will probably take us 30 years to level off and
come to the standards of the western countries. So let the
government and the medical community start acting now.
SUGGESTED
READING
1.
Stallerman G.H., Rheumatogenic Group A Streptococci and the return of
Rheumatic fever. Advances In Internal Medicine 1990;35:1-26.
2.
Padmavathi S„ Rheumatic Fever and Rheumatic Heart Disease in India:
Progress In Cardiology (Yu and Godwin): 13:169-183.
3.
Stallerman G.H. In Braunwald Text Book - Heart Disease 3rd Edition:
Pg 1706-1717
35 —
CARDIOLOGY - SYMPOSIUM
St. John's Medical College Journal of Medicine
MANIFESTATIONS, DIAGNOSIS, TREATMENT AND
PREVENTION OF RHEUMATIC FEVER
PRADEEP K. SHETTY
Eva, Eva, with rising fever
What does your work up show?
Is there arthritis
A touch of St.Vitus
How high is your ASO?
The sounds I hear, I fear, my dear
Mark regurgitant flow
But Jones Criteria
Have yet to appear in ya
So you are still an F.U.O.
- ‘Anonymous medical student’.
The often quoted decreasing incidence of Rheumatic fever in
the western and Scandinavian countries definitely does not
hold true for the population of under privileged third world
countries. The annual incidence of 142/100000 in the 519 age group and 47/1,00000 for the general population, as
reported from Sri Lanka probably reflects a similar incidence
of Rheumatic fever in India. The enormity of the problemsof- both Rheumatic fever and its sequelae can be gauged
when the size of the country and its large population are
considered. So it is not untimely that we review the problem
of rheumatic fever, so that the diagnosis is not missed, the
problem is treated appropriately, and the late complications
are avoided.
CLINICAL MANIFESTATIONS
The signs and symptoms of acute rheumatic fever are
subject to wide variations in qualitative and quantitative
expression and are determined by the systems involved,
the stage and the time duration of the disease process, at
which the patient first sees his physician.
Although arthritis is emphasized in its name, carditis is the
most serious manifestation, which can cause death during
an acute attack and can lead to residual disability and late
mortality, where as arthritis is short lived and generally leaves
no sequel. Carditis and arthritis along with chorea,
subcutaneous nodules and erythema marginatum have
been called major manifestations, which is not due to their
importance in severity or their relationship to prognosis but
because of their importance as diagnostic criteria. They
DR.PRADEEP.K.SHETTY M.D..D.M
DEPARTMENT OF CARDIOLOGY
STlJOHN'S MEDICAL COLLEGE & HOSPITAL
BANGALORE - 560 034
36
occur with a frequency far exceeding chance following
streptoccal infection. Minor manifestations are too non
specific to be of major use but can be of help in recognising
the disease. These are fever, arthralgia, acute phase
reactants, heart block and past history of acute rheumatic
fever or rheumatic heart disease.
Arthritis : Among the major criteria polyarthritis is the most
frequently encountered in about 75% of patients particularly
in older children and adults. The joints manifest tenderness
and painful limitation of motion. Although patients with
acute rheumatic fever may have involvement of a single joint
they usually progress to involve more large joints of the
extremities. Most often involved joints are knees, ankles,
elbows, and wrists. However, the small joints including
temporo mandibular joint and those of the vertebrae may
be affected. Pain
in rheumatic arthritis is often
dispropotionate to the objective signs. Several joints are
involved in quick succession resulting in typical picture of
migratory poly-arthritis. Inflammation generally lasts 2-3
weeks. It seldom occurs more than 5 weeks after the
streptococcal sore throat. It is almost always associated
with rising or peak titre of streptococcal antibodies which is
of diagnostic importance. There are no residual deformities
following rheumatic poly-arthritis except in the variety of
Jaccouds arthritis reported
from the Scandinavian
countries. This form of arthritis is characterised by deformities
of the fingers due to erosion of metacarpal heads and
metacarpophalyngeal joints resulting from periarticular
fibrosis giving rise to characteristic hook like deformities.
Carditis : Carditis is the most important and most serious
manifestation of rheumatic fever. Incidence of carditis in first
attack of rheumatic fever is said to be in the range of 64-80%
in developing countries, more frequently seen in the young
and it is an early manifestation. A murmur can be heard within
two-three weeks in 85% of the patients with carditis. Severity
of carditis can vary from subclinical to death. There has been
a decline in the incidence of carditis. Presence of one or
more of the following features is essential in diagnosing
carditis. - (1) an organic heart murmur or murmurs not
previously present. (2) cardiac enlargement (3) cardiac
failure
(4) pericarditis associated with rub or signs of
effusion.
Murmur - Murmur of mitral and aortic regurgitation are
frequently heard. The former is thrice as common as the latter
in patients with acute carditis. Involvement of the tricuspid
valve is very rarely recognised. A short low pitched mid
diastolic murmur may be heard at the apex (carey coomb’s
murmur) which is said to be due to swollen leaflets secondary
vol in No. 2 —
St.
John’s Medical College Journal
of Medicine
to mitral valvulitis. Presence of murmurs add to the risk of
permanent valve injury. In some the murmur of mitral
regurgitation can disappear completely with time.
Cardiomegaly : Cardiac enlargement of over 50% of
cardiothoracic ratio is an indicator of myocarditis, and is
of prognostic importance. The presence of pericardial
effusion may add to the increase in cardiac size in addition
to the dilatation of the cardiac chambers. Assessment of
cardiac size periodically is important for follow up of patients
with acute rheumatic fever and carditis.
Cardiac failure: Commoner with rheumatic recurrence than
with a primary attack. Though it occurs in less than 10% of
patients with carditis and is the least common, it is the most
serious manifestation of rheumatic carditis. Cardiac failure is
secondary to the combination of myocarditis and valve
insufficiency. Its recognition may be difficult in small
children.
Pericarditis - occurs in 5-10% patients with rheumatic
fever, especially in patients with severe carditis, Pericardial
effusion is rarely large in patients with rheumatic pericarditis.
Subcutaneous nodules - They are rare under the age of 3
years and again in adults. They are much more frequent in the
presence of carditis than in its absence. Though the
incidence of subcutaneous nodules was up to 30% earlier,
now it is seen in less than 10% of patients with rheumatic
fever.
Subcutaneous nodulus
are a relatively late
manifestation of rheumatic fever, usually occuring several
weeks after the onset. The subcutaneous nodules are firm,
painless, discrete, mobile measuring 0.5 to 2 cm in diameter.
They are commonly located over the extensor aspect of
elbows, knees, ankles, knuckles, spinous process of
vertibrae, and in the occipital region. They occur in crops and
tend to be symmetrical. Most of the nodules disappear in
1-2 weeks. They tend to be smaller and less persistant
than rheumatoid nodules.
Erythema marginatum - This occurs in less than 5% of
patients with acute rheumatic fever. It is usually associated
with carditis. It is not pathognomonic of rheumatic fever and
may be seen in sepsis, drug reactions and in patients with
glomerulo nephritis. Erythema marginatum are pink macules
commonly seen on the trunk and proximal part of the
extremites. They are evanescent, non pruritic and non
painful, begin as enlarging rings which later fuse to form
serpigenous patterns. The lesions blanch completely on
pressure and may be accentuated by hot bath.
They generally occur early in the course of the disease but
may recur for months, when all other signs of rheumatic
activity have disappeared.
Chorea : Chorea does not occur in patients under 3 years of
age and becomes rare after puberty. When seen in adults it
is seen only in pregnant women. It has a female predilection
----
JUNE 1990
------ —------------- - -------------------------------------
which increases after puberty. In the last 50 years its
incidence has decreased from the proximity of 50% to less
than 5%. There is usually a latent period of several months
usually 1 to 3 months. The onset is insidious, characterised
by emotional lability, irritability and clumsiness as its earliest
manifestation. Chorea may present as the only manifestation
of the disease, when it is called pure chorea. Chorieform
movements are rapid, jerky, irregular, non repetitive and
purposeless.lt is particularly dominant in the muscles of the
upper limb and face, worsened by excitement and fatigue.
It promptly disappears with sleep. Muscular hypotonia,
varying degrees of weakness of muscles and staccatto
speech are the features noticed in
neurological
examination. Chorea may last from 1 week to 2 years (on
an average lasts for 2 to 4 months). It is never seen
simultaneously with arthritis but may be seen in association
with
carditis. Rheumatic heart disease develops in
approximately 25% in 20 years in patients who have had
chorea as a manifestation.
Following are some important diagnostic signs associated
with chorea. These are
1. Pronation sign :- Raising the arms above the level of the
head causes pronation of both hands.
2. Spooning :- When hands are held out, there is flexion of
the wrists, hyperextension of metacaropophalyngeal joints
and abduction of thumbs.
3. Milkmaids grip : When asked to squeeze the examiner’s
finger the patient is unable to maintain a sustained grip.
4. Jack in the box tongue :- When the patient is asked
to protrude the tongue, it is shot out and withdrawn at high
speed.
MINOR MANIFESTATIONS
1. Fever and tachycardia are usually present at the
onset of acute Rheumatic fever. Tachyeardia may be
disproportionate to the degree of fever. Fever in Rheumatic
fever has no characteristic pattern and rarely exceeds 104°F
and lasts approximately a week without antipyretic
treatment. When antirheumatic treatment is used, a
rebound of fever may occur after 4-6 weeks of treatment but
it usually subsides spontaneously within a few days.
2. Epistaxis: Occurs in less than 5% of patients. Abdominal
pain may herald the onset of acute rheumatic fever, posing
thereby a diagnostic dilemma. This is seen in less than 5%
of patients and is said to be related to mesenteric vasculitis
or adenitis.
3. Rheumatic Pneumonia is very rare now. It may occur
in patients with long standing rheumatic disease with
severe carditis and implies a grave prognosis.
4.
The ST changes and PR prolongation are nonspecific
-------------------------------------------------------------------------------
37—
St. John's Medical College Journal of Medicine
acute rheumatic fever, various criteria have been proposed.
The well known criteria of Jones have survived, albeit with
certain modifications. Jones criteria originally described in
1944, were modified by the American Heart Association in
5. Lab Data - Evidence supporting a recent streptococcal 1956, when arthralgia was relegated to a minor status. In
infection or a history of recent scarlet fever are essential in
1965 the necessity of demonstrating recent streptococcal
making a diagnosis of rheumatic fever.
infection
was included. In 1984, the exclusion of
nonrheumatogenic aetiologies of chorea were stressed. It
(i) Throat culture : All patients with suspected rheumatic was also recognised that an elevated ASO titre could result
fevershould have athroat culture. However the cultures are
from an infection with the Non-group A streptococci
often negative by the time rheumatic fever appears. A positive
infection, in addition to streptococcal skin infections.
culture may represent a carrier state rather than an
antecedent infection.
If supported by antecedent streptococcal infection,
and are of no prognostic significance. The diagnosis of
Rheumatic Carditis should never be based on ECG changes
alone.
(ii) Test for streptococcal antibodies - The ASO (Anti
Streptolysin O) titre begins to rise in 1 -2 weeks and peaks at
3 weeks. ASO titre and ADNB are specific antibodies
primarily used to diagnose streptococcal infections. A
significant rise in ASO titre was found in 80% of patients
with acute rheumatic fever. The prior institution of therapy,
differences in host response, and different strains of
streptococci are important in determining the magnitude of
the ASO response. Antibody titres fall off rapidly till 6 months,
and then level off.
Polyarthritis always occurs within 4-5 weeks of the
antecedent
streptococcal infection and therefore the
antibody response is at its peak. Titres of 333 Todd units or
greater in children and of 250 Todd units orgreater in adults
are commonly found in the acitive phase of acute rheumatic
fever.
(iii) ADNB is highly reproducible and useful. It remains
elevated for a longer period than the ASO titre. Hence it is a
useful test in late manifestations like chorea.
(iv) The Anti NAD-ase test though useful is not freely
available commercially. The Anti Streptozyme test (ASTZ)
is a simple agglutination test available for detecting
streptococcal antibodies and has been referred to as an
universal antibody test. It is also a very sensitive measure of
the host’s anti streptococcal immune response and helps
to rule out rheumatic fever if negative.
(v) Acute phase reactants-these inculdetotal leucocyte
count, ESR, C-reactive protein (GRP), serum mucoprotein,
and serum hexosamine among several other tests. Most
important of these are the ESR and CRP. ESR is always
accelerated in rheumatic fever without therapy. However,
the ESR may not be elevated in patients with heart failure
or patients who are on corticosteroid therapy. CRP is so
named because of its reactivity with the ‘c’ polysaccharide
of the pneumococcus. It is a globulin which rises during the
course of any active inflammation. It can be measured semiquantitatively, and Is unaffected by anemia or heart failure.
DIAGNOSIS
To bring a certain degree of uniformity to the diagnosis of
38
demonstration of increased streptococcal antibodies in the
serum, two major or one
major
and two minor
manifestations indicate a high probability of acute rheumatic
fever.
As all patients with Sydenham’s chorea have a rheumatic
etiology, a diagnosis can be made even when chorea is
the sole manifestation.
Jones criteria (Revised)
Major
Manifestations
Minor
Manifestations
1. Carditis
1. Fever
2. Polyarthritis
2. Arthralgia
3. Chorea
3. Previous Rheumatic Fever
or Rheumatic heart disease
4. Erythema
marginatum
4. Elevated ESR or positive CRP
5. Subcutaneous
nodules
5. Prolonged PR internal on an
ECG
In addition supporting evidence of preceding streptococcal
infection: A history of recent scarlet fever; positive throat
culture for Group A streptococci; raised ASO titres, or
demonstration of other streptococcal antibodies, must be
present.
Arthralgia as a minor criterion, can create problems in
diagnosing rheumatic fever (Bhattacharya and Tandon).,
namely;
1) Patients of Rheumatic heart disease who have fever,
arthralgia, prolonged PR internal even with evidence of recent
streptococcal infection.
2) Patients with post streptococcal arthralgia with other
minor criteria.
VOL HI No. 2 —
St. John's Medical College Journal of Medicine
Disorders that simulate arthritis of Rheumatic fever
suppress the later appearance of definite arthritis or fever.
4) Acute reactive arthritis following infection elsewhereespecially with Yersinia enterocolitis, Rubella.
(2) Patients with definite arthritis with or without associated
mild carditis should be treated with aspirin, in the absence of
cardiomegaly or CHF.
3)
5) Collage diseases (eg., Rheumatoid arthritis and SLE).
Lyme arthiritis, viral hepatitis, gonococcal arthritis, sickle cell
anemia
can
pose problems in
diagnosis.
Viral
myopericarditis, atrial myxoma and infective endocarditis
can mimic several features of acute rheumatic fever.
TREATMENT
Mainly supportive
1.
Eradicate streptococcal sore throat
2.
Suppression of inflammation
3.
Control of CHF and chorea
4.
Prevent recurrences.
ERADICATION OF STREPTOCOCCAL SORE THROAT :
Once the diagnosis is established, all patients should be
given therapeutic course of penicillin adequate to eradicate
residual group a streptococci. A single injection of 1.2 million
units of Benzathine Penicillin is sufficient. Alternatives are
1.
IM procaine pencillin 6 lakhs for 10 days
2.
Penicillin G oral 2.5 lakhs 4 times a day for 10 days
3.
Penicillin V 250 mg .1 D x 10 days
SUPPRESSION OF INFLAMMATION : Bed restPatient
should remain in bed for the duration of acute and febrile
period of the illness until clinical and lab evidence of
inflammation abates. Gradual ambulation for three weeks
following three weeks of bed rest is recommended for fever
and arthritis. When carditis is present additional 2 weeks of
bed rest are required. When carditis with cardiomegaly
exsists 6 weeks bed rest and when carditis with CCF is
present, bed rest till control of failure is necessary.
Restricted physical activity is continued until a month after
anti inflammatory treatment is stopped, (usually 8-12 weeks
of treatment). Suppressing inflammation does not shorten
the course of illness and does not prevent carditis or reduce
the incidence of cardiac damage but it controls the
inflammation and symptoms. Fever, arthritis and pericarditis
may respond dramatically. Most physicians tend to treat
carditis with steroids.
Guidelines useful for suppression of inflammatory
process when planning treatment for various subsets
of patients with acute rheumatic fever are
(1) patients with arthralgia or mild arthritis and no evidence
of carditis should initially be given simple analgesics like
codiene especially when diagnosis is in doubt so as not to
JUNE 1990
(3) Patients with carditis and cardiomegaly but no cardiac
failure are usually treated with aspirin.
(4) Patients with carditis with cardiomegaly with or without
cardiac failure should be treated with corticosteroids.
(5) Carditis with long apical blowing systolic murmur of
more than grade 3/6 is usually treated with steroids.
(6) Patients with pericarditis are treated with steroids since
most have cardiomegaly or CHF.
(7) patients who develop carditis while they are already oh
aspirin therapy should be treated with steroids.
(8) Recurrent attacks of acute rheumatic fever with
established rheumatic heart disease should be treated with
steroids
(9) Anti inflammatory agents are not indicated in patients
with isolated chorea.
Salicylates inhibit prostaglandin synthesis. The dose should
be sufficient to achieve the level of 20-25 mg% (the dosage
usually required to achieve this blood level is 90-120 mg/kg/ *
day)
Adult patients require 6-8 gm/day in 6 divided doses. The
dose may be decreased to 2/3rd of the initial dose once the
clinical features of inflammation subside and halved when
acute phase reactants return to normal. The total duration of
treatment is 6-8 weeks. Prolonged treatment with aspirin may
result in hepatic injury which is reversible. Administration of
drug 30 minutes after meals and the use of enteric coated
preparations are beneficial in reducing gastric irritation and
bleeding. Use of antacids render the drug less effective.
CORTICOSTEROIDS - U.K., USA, joint trial of ACTH,
aspirin and cortisone in acute rheumatic fever using low
dosages of corticosteroids failed to show any advantage of
steroids with regard to residual damage at 1,5 and 10 years
after the initial attack.
However, in patients with acute rheumatic myocarditis or
pancarditis corticosteroids may be life saving. The usual dose
of cortisone is 60-120mg in adults. The dose may have
to be increased if no improvement occurs in clinical or lab
parameters within a week. High dose steroid should be given
for the first 1-3 weeks, then tapered over 1-2 weeks. While
steroid is being withdrawn aspirin is added to the treatment
in standard dose to avoid rebound.
Post treatment rebound - mild rebounds generally abate
within a few days and require simple analgesis or aspirin. In
39 —
St. John's Medical College Journal of Medicine
severe cases aspirin in full dose may be required for 3-4
weeks.
Control of heart failure - Bed rest, salt restriction, diureties
form the usual treatment of heart failure. Vasodilators may
be added in severe regugitant lesions. Valve replacement
may save many lives in patients with intractable heart
failure.
Chorea - Corticosteroids and aspirin are ineffective in
the treatment of chorea. Rest, quiet environment, chlorpro
mazine 25 mg and phenobarbitone 15-30 mg every 8 hours
form the line of treatment of chorea.
Course and prognosis - The latent period between
streptococcal infection and onset of acute rheumatic fever is
shortest in arthritis and E. marginatum and longest in chorea.
The usual duration of rheumatic fever is rarely longer than
3 months. In less than 5% of patients the acute rheumatic
fever may persist for longer than 6 months. These cases
are called chronic rheumatic fever.
Carditis - The incidence of carditis before the age of 3
years is 92% in patients with acute rheumatic fever. This
decreases to around 50% in 3-6 year age group and 32% in
14-17 year age group. Carditis occurs occasionally after the
age of 25 in apparent first attacks of acute rheumatic fever
whdn carditis is mild and it disappears rapidly. The prognosis
is excellent for the subject who does not develop carditis. The
patients who did not develop carditis, subsequently had
normal hearts in 96% at 5 years and 94% at 10 years.
Patients who developed CHF during acute attack have a
poor prognosis. Patients with CHF show complete healing
only in 30% at 5 years. Studies have shown that at 5 years
the frequency of mitral stenosis was equally distributed
between the sexes and was related to the severity of initial
attack of carditis. The analysis at 10 years showed the
emergence of another group i.e. those who initially had mitral
lesion that was mild and those who showed slow progressive
obstructions with recurrence of acute rheumatic fever. This
group consisted of predominantly female patients. In
preprophylaxis days, 25% of patients were dead within 10
years of the initial attack and of the remainder two-third had
heart disease. In contrast the patients who are on
prophylaxis the death rate 7-10 years after the onset is 10%
and two-third have no residual heart disease. With
increasing severity of initial carditis the prognosis becomes
poorer. In a ten year follow up study of 115 patients of
rheuamtic
fever on prophylaxis the murmur of mitral
regurgitation disappeared in 70% of patients and the aortic
regurgitation murmur disappeared in 20% of patients.
Prevention - Primary prophylaxis - Treatment
of
streptococcal infection with penicillin has been shown to
decrease the occurence of acute rheumatic fever from 3%
to 0.3%. Primary prevention means identifying patients with
40
group A streptococcal pharyngitis and treating these
appropriately. Though highly effective when it can be
administered, prophylaxis of first attacks is hampered by
huge size of the population at risk and by the difficulties
in diagnosing streptococcal pharyngitis. Classic features
of streptococcal infection are fever, fiery red throat,
patches of exudate and tender lymph nodes. Throat cultures
when negative are helpful in ruling out streptococcal infection
but converse is not true. A single IM injection of Benzathine
penicillin 6 lakh units in children under 27 kgs and 1.2 million
units in patients over 27 kgs is the treatment of choice when
the risk of rheumatic fever exists. Ten days of treatment is
essential if penicillin is administered orally. Chloramphenicol
or sulpha should not be used for primary prophylaxis.
Secondary Prophylaxis : The term secondary prophylaxis
means protection against rheumatic recurrences by means
of
continuous chemoprophylaxis. The importance of
secondary prophylaxis can be assessed by the fact that
death rateJor patients on secondary prophylaxis 7-10
years after onset of rheumatic fever is 10% when compared
to 25% mortality in the pre antibiotic era. One of the
following schedules for long term prophylaxis may be used.
(1) When IM Benzathine Penicillin 1.2 million units is given
every 4 weeks an attack rate of less than 1 recurrence per
250 patient years was documented. This form of prophylaxis
was used in the study conducted by Irvington house
group. 3 weekly schedule of Benzathine penicillin may be
more effective in high prevalence areas.
(2) Sulphadiazine 0.5 Gm per day for children weighing less
than 27 Kg and I Gm per day for patients weighing over
27 kgs.
(3) Buffered penicillin G2 lakhs to 2.5 lakhs twice daily - 30
minutes to1 hour after meals or pencillin V125-250 mg twice
a day. Oral prophylaxis is less reliable than repository
pencillin prophylaxis and has recurrence rate of almost 1 per
25 patient years.
(4) Erythromycin 250 mg BD for the rare patient who is
allergic to both penicillin and sulphadiazine. Although risk
of recurrences declined with age and with increased interval
from the last rheumatic attack, a relatively high recurrence
rate persists for a very long time. The duration for which
secondary prophylaxis
is administered should be
individualised. Generally in patients with chronic valvar
rheumatic heart disease, secondary prophylaxis should be
continued life long or at least upto the age of 40 years. Those
patients with cardiac involvement in the initial attack should
continue prophylaxis atleast till the age of 25 years but
longer if warranted.
Streptococcal vaccines : A satisfactory and safe vaccine
effective against prevalent group A streptococci has not yet
been developed. However streptococcal M protein, the only
VOL HI No. 2----
St. John's Medical College Journal of Medicine
antigen that stimulates protective antibodies have been
studied extensively and significant progress has been made
in purification of M proteins. These developments hold
promise for future vaccine development.
2. Gen. H. Stollerman in Heart disease - Editor-E.Braunewald, 3rd Edition,
-1988.
Acknowledgement : I sincerely thank Dr. Sunita Awasthi
for her kind help in preparing this article.
4. M.Thomas Abraham and George Cherian. Rheumatic
Cardiology. Editors - W.W Parmley and Kanu Chatterjee.
3. G.Disdascio and Angelo Taranta - Rheumatic fever in chilren Am.Heart
Journal; vol99;635-655-May 1980.
fever
in
REFERENCES
5. S.Padmavathi: Rheumatic fever and Rheumatic heart disease in India;
Progress in Cardiology No. 15, Editors- N. Yu and John.F.Goodwin.
1. Lewis. W. Wannamaker and Edward L Kaplan in Heart disease in infants,
children and adolescents Editors - Arthur J.Moss and Forrest H.Adams 1983.
6. P.L.Wahi, A Grover. Rheumatic fever. A Challenge Indian Heart - Journal
39,6,1987; 1-6.
FORTHCOMING SYMPOSIA
OCTOBER
-
1990
MEDICINE SYMPOSIUM
CURRENT ASPECTS ON DIABETES MELLITUS
DECEMBER
-
1990
DERMATOLOGY SYMPOSIUM
ALLERGY
JUNE 1990
41 —
CARDIOLOGY - SYMPOSIUM
St. John's Medical College Journal of Medicine
SURGERY FOR RHEUMATIC VALVULAR DISEASE
S.V. SRIKRISHNA
“ Any surgeon who wishes to preserve the respect of his
colleagues would never attempt to suture the heart”1 said the
great Billroth in the early 1880s. But perhaps just a few years
later with the successful suture of a wound in the heart by
Rehn in 1896, this myth was abolished and cardiac surgery
evolved as a speciality. The early surgeons had to overcome
many dogmatic views and superstitions. Most of the early
surgeries were heroic measures when the patient was to all
intents and purposes dead. It was thought fool hardy to
deliberately operate the inside of the heart of a patient who
was sick (a “medical case") and dream of
relieving
mechanical defects. Surgical correction of mechanically
deranged heart valves was put into practice first by Cutler in
1923 followed by Souttar in 1925. Digital closed
commissurotomy was pioneered by Bailey and Harken and
was further refined
by Logan and Turner. With the
development of the Heart Lung Machine in 1953 by Gibbon
Open Heart Surgery became a reality and surgeons could
now operate on a quiet, bloodless heart under direct vision.
Thus, the open reconstructive procedures were devised,
and, further led on to artificial heart valve implantations
following the pioneering efforts of Hufnagel, Harken and
Starr who in 1961 performed the first successful artificial
heart valve implantation. Since then there has been a rapid
progress in the surgical techniques and improved results
of cardiac surgery.
With this brief historical survey attempt is made only to give
a broad overview of what surgery can offer to treat valvular
heart disease. This also brings to the mind one single
important question - “when should valve surgery be
performed." The simplest way to answer this could be “Just
before the patients cardiac function becomes irreversibly
damaged.” Finding this ideal time is difficult and it is almost
always better to operate a little too early rather than a little too
late."
leaflets along commmissures, fibrosis of the leaflets and/or
subvalvar structures with stiffening, retraction and ultimate
calcification. This results in either stenosis or regurgitation or
a combination of both.
Mitral valve is the most common valve involved and is
affected in isolation in 50% of cases, Mitral and Aortic valves
combined account for 40%, Mitral, Aortic and tricuspid valves
in 5% and Aortic valve alone in about 2%. These valvular
lesions will be considered individually and the treatment
options discussed.
MITRAL STENOSIS
When the mitral valve orifice which is normally 4-6cm2 is
reduced to less than 2.0 cm2, patients
become
symptomatic due to increased leftatrial pressure, reduced
left ventricular inflow and thereby cardiac output and an
increase in the pulmonary vascular resistance. In addition
if the disease progresses without treatment, complications
such as Atrial fibrilation, systemic embolization, pulmonary
hypertesnion,
pulmonary infarction, chest infection and
Right ventricular failure ensues.
The decision for surgery is dependent upon the patients
symptoms, physical examination and laboratory studies.
Some patients who are asymptomatic or relatively
asymptomatic have much reduced valve areas, and this is
related to the fact that patients reduce their activity markedly.
The generally accepted indications for surgery in Mitral
stenosis are
1.
Patients in NYHA2
2.
Patients in NYHA class IV with greater risk
3.
Measured valve area of 1.0 cm2 or less
4.
Systemic embolization
Class II & III
RHEUMATIC VALVULAR HEART DISEASE
Rheumatic inflammatory process is a Pancarditis involving
the endocardium,
myocardium and pericardium, with
permanent injury almost always limited to the cardiac valve.
Rheumatic valvulitis causes distinct pathologic changes with
the degree varying among different patients - fusion of valve
DR.S.V.SRIKRISHNA, MS.MCH
DEPT. OF CARDIOTHORACIC SURGERY
ST. JOHNS MEDICAL COLLEGE & HOSPITAL
BANGALORE - 560 034
42
Effective commissurotomy can be achieved by a closed
method using a transventricular dilator guided into the valve
with an exploring finger in the left atrium. The pre requisites
for CMC are cases with pure stenosis without regurgitation,
pliable leaflets without calcification and absence of LA clots.
It is particularly useful in developing countries, in young
individuals, MS complicating pregnancy and in those with
concomittant trivial aortic valve lesions. Hospital mortality is
low 1.5%. About 0.3% develop severe MR3.
If the fibrosis extends down into the chordae tendinae and
papillary muscles, a careful subvalvar dissection and
separation of these structures under direct vision under
vol in No. 2 —
St. John's Medical College Journal of Medicine
cardiopulmonary bypass in a stationary blood less heart gives
optimum results. This open mitral valvuloplasty becomes
binding in the presence of atrial fibrillation, history of
embolisation, demonstrable clots in LA, mitral restenosis
and concomittant other valvar involvement requiring
surgery. In the present times operative mortality is as low
as 1 -3%.4-5 When mitral exploration reveals the presence
of extensive calcification or severe fibrotic deformity of the
valve, or there is a combination of regurgitation with
stenosis then it should be replaced with a prosthetic valve.
The operative mortality for pure MS is 1-4%.6-7
Recently a new technique- Balloon mitral valvuloplasty has
evolved. This technique consists of advancing a small
balloon floatation catheter across the inter atrial septrum
(after trans septal puncture), enlarging the opening and one
large (20-25 mm) or 2 small (12-18 mm) balloons positioned
across the mitral orifice and inflating them within the orifice.
The long term results of this procedure are still awaited.
As this is a progressive disease process the chances of
these valves becoming restenosed in about 2-60%0,9 is
noted, but generally it is between 2-10%.
MITRAL
REGURGITATION
This results from different types of structural injuries to the
mtral valve. These include leaflet retraction from fibrosis and
calcification, dilatation of the annulus, abnormalities of the
chordae tendinae (rupture, elongation or shortening) and
papillary muscle dysfunction.
The two major physiologic effects of MR are an elevation of
the left atrial pressure, and a chronic volume overload of the
left ventricle. The effects of left atrial pressure load are
usually reversible, but the effects of LV. Vol overload are
unpredictable and may not improve following an operation.10
It is therfore apparent that these patients should be referred
for surgery before they become severely symptomatic and
there is evidence of left ventricular dysfunction. The
indications for surgery are -
1.
NYHA class III or IV symptoms
2.
NYHA class II symptoms with
a)
LV diastolic minor axis dimensions 6 cms or more
b)
Regurgitant fraction 40% or more
c)
Severe MR with ejjection fraction 60% or less
d)
Increasing ventricular volumes or regurgitant
fractions.
There are no closed heart techniques and it necessarily
involves an open heart procedure, to correct MR. in order
to avoid producing iatrogenic prosthetic valve disease and
their complications, there is increasing enthusiasm to
JUNE 1990
perform reconstructive procedures depending on the defect
observed. The feasibility of repair is good if the leaflet is
pliable, with minimal fibrosis, no calcification and minimal
or absent subvalvar deformity and fibrosis.
a)
At the Annulus - Annuloplasty by suture or a prosthetic
ring in order to reduce the dilated annulus.
b)
At the cuspal level - wedge excision and repair of either of
the leaflets, or closure by a patch of a perforated cusp.
c)
At the chordal level - shortening or lengthening of the
chordae to correct prolapsed or retracted cusp.
As before, if the valve is severely damaged or with extensive
calcification a mitral valve replacement is performed. The
operative mortality for MR patients is about 2-7%6-7 and this
increases with the degree of left ventricular dysfunction.
AORTIC STENOSIS
Rheumatic fever affecting the Aortic valve in isolation is very
rare. Almost invariably there is a concomittant mitral lesion.
The gradient across the aortic valve leads to muscle
hypertrophy and wall tension. This in turn increases
myocardial oxygen consumption. But because of low aortic
pressure and increased resistance, coronary flow is
decreased and the overall
myocardial function
is
jeopardised. Significant symptoms appear quite late in the
course of the disease only when the normal valvular area of
3 cm2 is reduced to 0.5 cm2 or less. By this time the patient
has markedly shortened life expectancy. Patients with
Aortic stenosis and angina or syncope survive an average of
less than 3 yrs and those with congestive heart failure survive
an average of 1.5 yrs11 For this reason all symptomatic
patients with Aortic stenosis should have urgent operation
and medical therapy should be given only to stabilize the
patient before surgery. Presently the accepted indications for
surgery are 1.
Symptomatic patients - symcope, angina or congestive
heart failure
2.
Peak systolic gradient of 50 mm Hg or greater
3.
Valve index 0.5 cm2/m2 or less.
Since almost always the valves in aortic stenosis are thick,
fibrosed and often calcified valvotomy may not be feasible
and an Aortic valve replacement becomes invariable. This
may be combined with procedures on the mitral or tricuspid
valve as necessary and also in the elderly coronary bypass if
need be.
The operative mortality for AVR is around 2-8%, but if the
LV dysfunction has occurred, or additional procedures are
done then this would mount upto 10-25%.12
AORTIC REGURGITATION
As with MR, AR causes volume overload of Left Ventricle.
43 —
St. John's Medical College Journal of Medicine
The decision regarding the timing of valve replacement is a
very tricky one. Although it has been shown that medical
treatment can result in symptomatic improvement in patients
who demonstrate -LVF, valve replacement rarely improves
the abnormal LVF and abnormal compliance seen once
failure has occured. Patients with a syst BP > 140 and
diastolic BP < 40 plus LV enlargement and ECG evidence of
LVH, have an 87% chance of developing CCF or dying with
in 6 years.
one must be aware of the repercussions of replacing a
reparable but less than perfect native valve.
(a)
Ball & Cage -
Starr Edwards, Smell off cutter
If both CXRay and ECG indicate LV enlargement, patients,
even if asymptomatic, should have cardiac catheterization
performed, and if LV dysfunction is found, AVR should
definitely be undertaken. Actually it is preferable to undertake
AVR while EF is clearly normal, or even better supernormal,
since this indicates that the LV is functioning well and that the
response to surgery will be maximal with the lowest surgical
mortality.
(b)
Tilting disc
-
Omniscience, Medtronic Hall
(c)
Bileaflett
-
St.Jude Medical, Carbomedies
Recently end systolic Vol. as estimated by echo and cine
angiohas been used to predict the outcome of surgery, and
it may indeed serve as the most accurate indicator of when
to operate on asymptomatic individuals.
Although reconstructive procedures have been described for
AR in the form of plicating the leaflets with pledgeted
sutures, by and large most patients will require Aortic valve
replacement.
TRICUSPID VALVE DISEASE
Very often MV disease is complicated with - TR. It is
important to differentiate both functional and organic
disease. If regurgitation is found at cardiac cath, the
tricuspid valve should be directly visualized during open
heart procedure. At that time, if the valve leaflets are fine and
not involved with rheumatic endocarditis and the degree of
TR is massive, even if functional, it is generally necessary
to perform an annuloplasty, or at times replace the valve.
Sometimes organic TS may be the result of the rheumatic
process or an organic TS may be associated with TR. Again
if the valve is good commissurotomy is possible. However if
the valve is badly damaged the tricuspid valve may also have
to be replaced.
PROSTHETIC VALVE SURGERY
Despite the trend toward reconstructing diseased valves
most patients ultimately will need a valve replacement. The
field of valve replacement has evolved over the last 3
decades tremendously. However till date there is no perfect
replacement to the native valve. It must be realised that valve
replacement amounts to giving the patient an iatrogenic
disease because prosthetic valves are inherently
susceptible to thrombosis, embolism, endocarditis, valve
deterioration and
frequently
the complication
of
anticoagulation. Therefore before deciding to take this step
---- 44 ------------------------------- ----------------------------------------------
The currently available
classified as
heart valves
can
be broadly
MECHANICAL
BIOLOGIC
-
Carpentier Edwards
St.Jude biological
Hancock
The various aspects of each can be broadly summarized as
follows :-
Feature
Noise
TE
Anticoagulation
Endocarditis
Durability
Haemodynamic
Cost
Tissue
Mechanical
0
0-1%
0
+
6-10 yrs
++
+
++
3-5%
+
++
10-20 yrs
+
++
Durability is the forte of mechanical valves, but they are prone
to thromboembolic complications and require life long
anticoagulation while on the other hand tissue valves though
overcoming anticoagulation problems have a shorter life and
are prone for degeneration and calcification.
Therefore the choice of a valve should be critical weighing
the advantages and disadvantages of the different types of
valves and also taking into account the socioeconomic
factors, age and sex of the patients.
As a general guideline, biologic valves are most suitable for
1. Patients with contraindication to anticoagulation
2. Elderly patients in aortic position, where chances of
reoperation are remote
3.
Patient who is unreliable or has strong aversion to taking
Coumadin.
4.
Occassionally in women in child bearing age who have not
yet completed their family.
Mechanical valves are more suited for
1. All young individuals who may have a long life span
------------------------------------------------- -------- vol m No. 2—
St. John's Medical College Journal of Medicine
2. Patients who economically may not afford reoperations
3. Reliable compliant patients who can take anticoagulants
regularly
PAEDIATRIC VALVE SURGERY
Finally a few words about valve surgery in the paediatric age
group who are somewhat different from the adults. Hearts
of infants and children will grow with the child, but prosthetic
valves do not grow. Therefore, valve replacement in the
paediatric age group usually necessitates reoperation and
replacement of the valve at a later date. For this reason, a
lesser than perfect native valve that retains growth potential
is almost always betterthan the more perfect haemodynamic,
but temporary result, that might be obtained with a prosthetic
valve. Also anticoagulation in children is a problem with
regard to patient compliance as well as dose adjustments.
Consequently valve replacement infants and children is
generally considered a last resort.
REFERENCES
1. Robert G. Richardson : The Surgeon's Heart - A history of Cardiac
Surgery. William Heinemann Medical Books 1969
3. John S, Bash! VV, Jairaj PS etal. Closed mitral valvatomy: Early results
and long term follow up of 3724 consecutive patients Circulation
1983;68:891.
4. Gross Rl, Cunningham JN Jr; SnivelySL et al. Long term results of Open
radical mitral commissurotomy Ten yr follow
up study of 202 patients.
American J.Cardiol 1981;47:821.
5. Coher LH, Alfred EN, Cohen LA: et al. Long term results of Open mitral
valve reconstruction for mitral stenosis. Am.J.Cardiol 1985;55:731.
6. Bjork VO, Henze A, Lindblom D: The current status of prosthetic valves
in mitral position. In Duran C & Angels W W, Johnson AD &Oury J.H. (eds).
Recent progress in mitral valve disease, London, Butterworths 1984. pp.201210.
7. Jepsy JF, Grumkemeier G, Sutherland H D'A et al. the ultimate prognosis
after valve replacement. An assessment at 20 yrs. Ann. Thorac Surg.
1981;32:111.
8. Arora R, Khalilullah M, Gupta MP & Padmavati S, Mitral restenosis,
Incidence and epidemielogy Indian Heart J. 1978;30265.
9. Heger HJ, Warm LS, Weyman AE, Dilton JC & Feigerbamm H. Long term
charges in mitral valve area after successful commissurotomy. Circulation
1979;59:443.
10. Braunwald E: Heart Disease - Text book of cardiovascular Medicne.
Chapter 31. Valvular Heart Disease. Philadelphia WB Saunders Co. 1980.
11. Frank S. Johnson A, & Ross J.Natural history of valvular Aortic stenosis.
Br. Heart J 1973;35:41-46.
2. Goldman et al. Comparitive reproducibility and variability of systems for
assessing cardiovascular functional class: advantages of a new specific
12. Kirklin J.W & Barratt Boyes BG. Aortic valve disease in Cardiac Surgery,
activity scale. Circulation 1981 ;64:1227
Newyork. John Wiley & Sons 1986. p.374-420.
JUNE 1990
45 —
ORIGINAL ARTICLE
St. John's Medical College Journal of Medicine
VERTICAL VERSUS HORIZONTAL IMMUNISATION
AMONG TRIBAL COMMUNITIES
ABBEY JOHN PERUMPANANI
SUMMARY :
The study compares the efficiency of vertical versus horizon
talimmunisation programmes in its applicability to tribal
communities. It was found that horizontal strategies resulted
in better coverage rates given the peculiarities of tribal
populations.
tribal development. This includes a residential school,
vocational training institute, adult education programme,
tribal co-operative society, a ten bedded hospital, outreach
programmes etc. Because of its intimate involvement in all
these spheres the organisation enjoys the popular support
of the community. Also the tribal leaders are involved in
every stage of planning making the execution of such a
project acceptable to the community.
INTRODUCTION :
Spurt in developmental activities among tribal communities
is bringing them closer to the mainstream of life. This also
entails the risk of exposure to infections from which they have
hitherto been barricaded consequent to their isolation. Urgent
action is called for to achieve quick immunisation coverage
so as toprecede the impact of developmental activities.
This study analyses the impact of a horizontal immunisa
tion programme carried out in such a community and the
result of a concurrent evaluation of the vertical clinic-based
immunisation hitherto operative.
MATERIALS AND METHODS
Kollegal is the largest taluk in Mysore District of Karnataka.
It has a tribal population of 15,834 (1987 census) and has a
rather low under five population of 730. The high rates of
infant and perinatal mortality in the absence of earlier
comprehensive maternal and child health care probably
explain this. They live in isolated groups called ‘Podus’ each
having 50-120 families. There are 40 such Soliga Podus in
Kollegal taluk.
We are a voluntary agency that has taken over their health
care for the past few years. Until then government agencies
have been responsible for their health care needs. The
agency involves itself comprehensively with all aspects of
One member from each Podu was selected and during an
orientation programme at our hospital was told in detail
about the need for vaccination, the benefits that accrue from
it and the proposed plan. The selected men were to conduct
a survey of the under five population in their respective
Podus. All data was collected from them and compiled
in a central register. The residents of each Podu were
informed of the date and time of the visits to their Podus for
the next three months.
The team for the vaccination programme was divided into
two groups, each self sufficient to carry out immunisation.
DPT and OPV were collected from the central store in
Mysore and stored in a hospital at Kollegal. Over a period of
two days the first phase of vaccination was completed. The
same was repeated twice more at monthly intervals. During
the first visit a survey was conducted of the vaccination
hitherto received.
RESULTS
Survey of the immunisation coverage so far achieved by
the existing vertical programmes was found to be 1.6% (12
out of 730) for this tribal group.
Coverage rates at the end of the horizontal programme
were as high as 90.1% for three doses of DPT and OPV
DISCUSSION
ABBEY JOHN PERUMPANANI
MEDICAL OFFICER,
JAYA VIJAYAM TRIBAL HOSPITAL
B.R. HILLS, MYSORE DISTRICT - 571 313
PRESENT ADDRESS :
DEPARTMENT OF ANATOMY
PSG INSTITUTE OF MEDICAL SCIENCES &
RESEARCH
COIMBATORE - 641 004
46
The epidemiologic advantages of horizontal immunisation
and the better sero conversion rates in rural communities
has already been reported ’.The advantages of annualpulse
immunisation to simplify cold chain management in develop
ing countries are also well documented.2-3 The model for
polio was originally suggested by Sabin4. However, its incor
poration inta the national strategy has not yet been done.
Though success has been claimed in several areas with the
present pattern of immunisation, isolated communities still
leave much to be desired as shown by this study. The study
recorded a coverage rate of 1.6% prior to its immunisation
programme. Also in the existing programmes maintenance
of the cold chain overcoming difficulties of terrain, transport
VOL III No. 2----
St. John’s Medical College Journal of Medicine
TABLE
COVERAGE RATES FOR DPT AND OPV AT THE END
OF HORIZONNTAL IMMUNISATION PROGRAMME
DPT & OPV
No. GIVEN
1
DOSE
670
(658 + 12)
91.7
II
DOSE
684
(658 + 26)
93.5
III DOSE
668
(658 + 10)
91.5
658
90.1 ‘
Overall coverage rate
for three doses
*
% COVERAGE
Some children who did not receive the first dose were given the second and third doses. 90.1% indicates those who received all there doses (658
children).
and power supply pose serious problems.
With the thrust of ongoing developmental activities among
tribal groups becoming tangible, they are increasingly coming
in contact with the mainstream of life. The resultant
exposure to new infections may affect large segments of the
population. Such hasoccuredin Hawaii and other areas when
Europeans came in contact with isolated groups.5 Urgent
action is hence necessary to immunise these groups. The
present strategy of immunisation will not suffice and hence
horizontal immunisation should be implemented to
telescope the duration required, increase rates of coverage,
achieve better sero-conversion and overcome the weak links
of the cold chain. Because this was the first year of the
programme children from 0-5 years were eligible for vaccina
tion.
A few problems were encountered during this programmed
The death of one child within a week of the first dose of DPT
and OPV following a diarrhoeal illness in one of the Podus
made the acceptance of the subsequent doses a little diffi
cult. Patient explanation by our social workers and others
prevented this from snowballing into a major problem. There
was one case of an injection abscess requiring surgical
treatment at our hospital. The people were warned of the
JUNE
1990
occurance of trivial febrile episodes following vaccination
and this was managed by them locally with antipyretics
provided to them at the time of vaccination. This did not
pose a significant problem.
Thanks are due to Dr.Kulkarni, Professor and Head of the
Department of Community Medicine, Mysore Medical
College for having delegated his house-surgeon for the
execution of this study. The vaccines were supplied by the
District Health Officer, Mysore.
REFERENCES :
1. John TJ, Joseph A, Rathnam PV: A better system for polio vaccination
in developing countries? Br. Med.J. 1980;281:542-543
2. John TJ. Stienhoff MC; Appropriate strategy for immunisation of children
in India : III Community based annual pulse (cluster) immunisation. Indian
J Pediatr. 1981;48:677-683.
3. Steinhoff MC. John TJ, Appropriate strategy for immunisation of children
in India: IV Measles and its control. Priority number one. Indian J Pediatr
1982;49:303-310.
4. Sabin AB, Vaccination against poliomyelitis in economically underdevel
oped countries, Bull WHO 1980;58:141-157.
5. Louise E Levathes. Steve Reyner, Herl Kawainui Kane: Kamehameha
: Hawaii's Warrior King. National Geographic; Nov. 1983;164:558-598.
47 —
REVIEWS
St. John’s Medical College Journal of Medicine
NEUROLOGICAL DISEASES WITH A PRESUMED IMMUNE
AETIOLOGY
JANE WELSH
INTRODUCTION
In the 1990s immunologists will be tackling two main ques
tions:- (1)How is tolerance to self antigens generated and
(2) How is tolerance lost in autoimmune disease?
Autoimmune diseases have a multifactorial aetiology
involving interaction between genetic background, environ
ment and infective agents. For these reasons, the exact
pathogenic mechanisms involved in autoimmune disorders
have evaded our understanding. However, during the past
two decades, the advances in the fields of immunology and
molecular biology, have contributed greatly to this particualr
field of medicine.
Perhaps the greatest impact on diseases of immune aetiol
ogy has been made by the observation that certain
major histocompatibiltiy antigens (MHC) occur at a higher
incidence inpatients with a particular autoimmune disease
(Table 1). For instance patients with HLADr2 have a relative
risk of developing multiple sclerosis which is 3.8 times that
of the non-Dr2 population. The majority of autoimmune
diseases show a stronger correlation with the presence of
certain Class II antigens which are the membrane glycopro
teins on macrophages, some T and B cells. Class II
antigens have been demosntrated to present antigens to
T cells and thus initiate the immune response (Babbitt et
al. 1985).
MECHANISMS OF AUTOIMMUITY
(1) Aberrant Class II Expression
In the majority of autoimmune diseases, with the notable
exception of myasthenia gravis, Class II expression has
been observed on abnormal cells at the site of the lesion
(Bottazzo et al 1983 and Feldmann, 1987). The expression
of Class II allows the presentation of autoantigens to T cells
(Londei et al 1984) and was thought to be the initiating event
in the subsequent development of chronic inflammation.
However, the most potent inducer of Class II is the T cell
factor, gamma interferon (Todd et al 1985) thus lymphocytic
JANE WELSH,
DEPARTMENT OF PATHOLOGY,
CAMBRIDGE UNIVERSITY,
TENNIS COURT ROAD,
CAMBRIDGE, CB2IQP
U.K
48
in-filtration of the target organ is thought to precede the
expression of MHC molecules (Walker et al 1986). The
aberrant Class II expression in autoimmune disease exac
erbates the lesion and may be an important factor in allowing
progression to chronic inflammation.
(2) Cross-re act ivty
Infection with a microrganism which carries antigenic
determinants similar to host antigens may result in autoreactive immune responses. Rheumatic heart disease develops
in some patients following infection with Streptococcus
pyogenes. This bacteria has antigens which are similar to
heart valve proteins and the inflammation is a result of
crossreactive antibody binding to heart valves (Kaplan and
Meyerserian, 1962). The causative microbe need not be a
pathogen as in the case of the chronic inflammatory disease,
ankylosing spondylitis. Although this is not a classical
autoimmune disease, it is associated with the presence of a
Class I antigen HLA-B27 (Table 1). 90% of these patients are
B27+ compared to 8% of the normal population (Brewerton
et al. 1976). This condition is thought to arise as a result of
cross reactions between B27 and a normal gut commensal
Klebsiella pneumoniae (Welsh et al. 1980).
(3)
Altered Antigens
Tolerance can be overcome by exposure to an altered self
protein or a similar protein from a related species. Prior to the
use of synthetic insulin, patients with IDDM received
injections of porcine insulin which differs from human insulin
by 1 amino acid. In some individuals this evoked the produc
tion of autoantibodies (Male et al 1987) to human insulin. The
general laboratory method for generating models of autoim
mune disease employs a similar technique; the autoantigen
is altered by emulsfying in complete Freund’s adjuvant
(CFA).
(4)
Idiotypic Networks
During the evolution of an immune response, novel proteins
arise as a result of somatic mutation of immunoglobulin
genes. Each new antibody acts as an antigenic stimulus and
results in the formation of an antibody or anti-idiotypic
antibody (jerne, 1974). A similar situation arises in viral
infection. If
we consider a virus as + then antibodies
generated against the virus will be - as will be cell bound virus
receptor. The anti-idotypic antibodies produced against the
antiviral antibody (-), will be + and will interact with them and
also the virus receptor. Thus a viral infection can initiate anti
receptor autoimmunity.
vol in
No. 2 —
St. John’s Medical College Journal of Medicine
TABLE OF RELATIVE RISKS ASSOCIATED WITH PARTICULAR HLA
ANTIGENS
DISEASE
HLA ANTIGEN
FREQUENCY IN POPULATION
PATIENTS
CONTROLS
RR
Haemachromatosis
HLA-A3
71
20
9.0
Ankylosing
Spondylitis
HLA-B27
90
8
87.8
HLA-Dr2
42
22
3.8
Multiple
Sclerosis
RR = Relative Risk
From Roitt I, Brostoff, J. and Male D. In Immunology Published by Gower Medical Publishing London 1986 p.4.11
GUILLAIN-BARRE SYNDROME
This condition is characterized by a monophasic acute or
subacute progressive ascending motor weakness which
may result in quadriplegia. It occurs at an incidence of 21
100,000 with a world wide distribution and peaks in young
adults and during the fifth decade of life (Steiner and
Abramsky, 1985). The disease is normally arrested in the
first 2-4 weeks and there is a recovery rate of 80-90%. In the
majority of patients there is a history of an antecedent viral
infection with measles, mumps, rubella, EBV, herpes, influ
enza A or B or bacterial infections of mycoplasma, salmo
nella,
listeria or brucella (Schumberg et al 1983),
Furthermore, the disease in some patients follows injections
with rabies or swine flu vaccines (Schonberger et al 1981).
The experimental model of this disease, experimental
allergic neuritis (EAN), involves the injection of peripheral
nerves in complete Freund’s adjuvant (waxman and
Adams, 1955). Cell mediated immunity is thought to be
important in both EAN and GB since in vivo sensitivity to
peripheral nerves arise in both conditions (Arnason, 1984).
Since herpes virus is known to infect nerves, it is possible
that sequestered antigens are then made available to the.
immune system. Perhaps the correlations with other infec
tion allow the recrudescence of herpes virus.
MYASTHENIA GRAVIS
Myasthenia gravis (MG) is one of the most well understood
autoimmune diseases. It is characterized by muscle weak
ness due to defective transmission at motor end plates of
skeletal muscle. 90% of MG patients have antibodies against
the acetyl choline receptor (ACR) (Ashizawa and Appel,
1985). MG can be induced in experimental animals by the
injection of ACR in CFA (Albuquerque, 1979). The disease
can be transferred using sera from affected animals and
JUNE
1990
patients (Toyka et al 1975) The absence of Class II
expression in the MG lesion and the lack of contribution of
autoreactive T cells, suggests that this disease is solely the
result of antibodies to ACR. The isotype of antibody
produced to the ACR antibodies are of the lgG3 isotype, they
mediate damage through complement fixing antibodies
cause increased degradation of receptors by cross linking
and blocking the cholinergic binding sites of the ACR. Cell
mediated damge may occur through antibody dependent
cellular cytotoxicity via Fcmacrophase interactions (Ashi
zawa and Appel. 1985).
The target antigen in a considerable number of
autoimmune diseases is the membrane bound receptor as is
the case for MG. Perhaps the most likely mechanism of
pathogenesis in this condition is a breakdown in-tolerance
by the anti-idiotypic network.
MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is a primary inflammatory demyeli
nating disease of young adulthood which occurs in females at
a slightly higher incidence than males. The aetiology of MS
is unknown although it is thought to be triggered by a virus
encountered in the first decade of life since children who
move from areas of low risk (tropical climate) to areas of high
risk (temperate climate) before the age of 15 develop the
same high risk incidence (Achenson 1977).
Autoimmune mechanisms are also involved in the patho
genesis of multiple sclerosis, Histological examination of
MS plaques support an immune pathogenesis since they
contain plasma cells, macrophages, lymphocytes and the
cerebrospinal fluid contains IgG (Traugott, 1984). There have
been a number of reports of T cells reactive to myelin
membrane components in MS patients (Brinkman et al 1981).
49 —
VOL III No. 2
Diagram illustrating the some of the mechanisms that may be
in the initiation of demyelination induced by Theiler's virus
involved
St. John ’s Medical College Journal of Medicine
(b) autoimmune demyelinatior
St. John's Medical College Journal of Medicine
The experimental model of MS is relapsing experimental
allergic encephalomyelitis (R-EAE) induced in rodents by the
injection of myelin membranes in CFA (Brown and
McFarlin 1981). The simlarities between R-EAE and MS
also point to an immune component of MS. However, in
a recent pulication, Hafler and colleagues cloned T cells
from MS patients and were unable to find any evidence of
autoimmunity (Hafler et al 1987a). The clones did not
proliferate in response to myelin basic protein or proteolipid.
They also examined the B gene rearrangements in the T cell
receptor of thier clones and found no common pattern
suggesting a polyclonal immunoglobulin bands inthe CSF
and the polyclonal T cell reactions in MS suggest that either
the patients are sensitized to mulitple CNS antigens or a num
ber of viruses could be involved in the initiation of this
condition.
to reduce the incidence of disease (Welsh et al 1987). The
T cells may be autoreactive or may cause tissue damage by
attracting macrophages into the lesion which mediate
bystander demyelination by secreting proteases that digest
myelin sheaths (Figure 1 c). This mechanism may account for
the lesion induced by TMEV in SJL mice which develop
heightened T cell responses to the virus (Clatch et al. 1985).
THEILER’S MURINE ENCEPHALOMYELITIS VIRUS - A
MODEL OF MS
Susceptibility to the demyelinating disease induced by this
virus is also partly controlled by the MHC Class I genes. Class
I MHC gene products are involved in the presentation of viral
antigens to cytotoxic T cells and which results in the cytolysis
of the virus infected cell (Figure 1 d). Animals with the H2-Ds
gene have the highest incidence of demyelinating disease
(Rodrrguez and David, 1985). It is interesting to note that this
is also the gene that predisposes animals to EAE and
demyelination induced by JHM virus. Abberant Class II ex
pression on astrocytes in susceptible strains of animals has
also been noted in TMEV and JHM virus-induced demyelina
tion (Massa et al 1987 and Rodriguez et al 1987). this may
allow the astrocytes to function as autoantigen presenting
cells and thus initiate the autoimmune responses to myelin
components (Figure 1e).
Theiler’s virus is a Picornavirus which is biologically similar
to poliovirus (Theiler, 1934). Following intracranial injection,
susceptible strains of mice develop a biphasic disease of the
central nervous system. In the early phase one month
post infection, mice develop signs of a polio-like disease as
the virus replicates in motor neurones. During the chronic
phase of the infection, 2-6 months post infection, the virus
persists in the oligodendrocytes and astrocytes and gives
rise to an inflammatory demyelinating disease which is both
clinically and histologically similar to MS (Lipton, 1975). The
mechanisms of demyelination are partly the lytic effect of
the virus on oligodendrocytes, the myelin maintaining cells,
and also the immune response to the virus. The study of the
pathogenesis of this laboratory model of MS may assist in the
elucidation of the aetiology of MS.
Mice that are resistant to the demyelination induced by this
virus appear to be able to clear the virus from the CNS during
the ealry infectiron thus preventing the establishement of a
persistent infection of the CNS (Chamorro et al 1986). One of
the factors controlling susceptibility to this virus is likely to be
the T cell repertoireresistant stains being able to recognize
a protective T cell epitope and thus clear the virus.
Bystander demyelination may also accou nt for the da mage to
nerve axons seen in this strain. However, in CBA mice the
lesion is less inflammatory in nature and there is preservation
of nerve axons (Blakemore et al 1988). Furthermore, this
strain of mice do not develop delayed type hypersensitivity
responses to the virus and so this mechanism is unlikely to
play an important role in demyelination in this particular
strain.
The scientific dissection of the immune response during
demyelination induced by Theiler’s virus has given insights
into the effect of different genetic backgrounds on the
disease process. These observations may have important
implications when attempting to analyse and treat such a
complex disease such as multiple sclerosis.
The author would like to state that the opinions expressed
in this article are her own and are merely speculative.
ACKNOWLEDGEMENTS
Once the persistent virus infection of the CNS is established,
demyelination may occur by a variety of mechanisms accord
ing to the type of immune response evoked (Figure 1).
Firstly, lytic virus infection of oligodendrocytes will lead to
lossof myelin(Figure 1a). This is probablythe most important
mecahnism in T cell deficient nude mice (Rosenthal et al
1986).
Autoimmune mediated demyelination has also been impli
cated in TMEV infection. TMEV infected mice develop
autoantibodies to myelin which may exacerbate the inflam
matory lesion (Figure 1b) (Welsh et al 1987). Furthermore,
immunosuppressive therapies including T cell depletion prior
to the onset of demyelinating disease, have been shown
-----
JUNE
1990
-------------- —------------------------------------------ -7^
Oh-T-
S, ' • f
CJR WELSH is in receipt of a grant from the
Sclerosis Society of Great Britain.
Multiple
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1. Acheson, E.D. Epidemiology of multiple sclerosis.
Bulletin 1977;33:9-14.
British Medical
2. Albuquerque, E.X. Eldefrawi, A.T. Oliveria, A.C. Copio, D.S. and Elderfraei ME. Myasthenia gravis animal model. Exp Neurol 1979;66-109.
3. Arnason, B.g.W. Acute inflammatory demyelinating polyradiculoneu
ropathy. In Peripheral neuropahty. Editors Dyck PJ et al Saunders, Philadel
phia. 1984;
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4. Ashizawa t and Appel S.H. Immunopathologic events at the endplate in
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immunoreacitive material and spinal fluid reactivity to basic protein. Neurol
ogy 1981 ;31,180.
5. Babbitt, B.P. Allen P.M. Matsueda G, Haber E. and Unanue, ER. Binding
of immunogenic peptides to la histocompatibility molecules. Nature.
1985,315-359.
22. Londei M. Lamb J.R. Bottazzo G.f and Feldmann M. Epithelial cells
expressing abberant MHC class II determinants can present antigen to cloned
human T cells. Nature 1984;312:639-641.
6. Blakemore W.F. Welsh C.J.R. Tonks, P. and Nash A.A. Observations
on demyelinating lesions inducedby Theiler's virus in CBA mice. Acta
Neuropathojogy, in press, 1988.
23. Male D.champion B and Cooke A. Chapter on Tolerance and Autoim
munity in Advanced Immunology pp 12.2-12.13. Publishers*. Gower Medical
Publishing. London. 1987.
7. Bottazzo G.F. Pujol-Borrell, R.Hanafusa, T and Feldmann, M. Role of
abberant HLA-DR expression and antigen presentation in the induction
ofendocrine autoimmunity. Lancet. 1983;2:1115-1119.
24. Massa P.T. ter Melulen V and Fontana A. Hyperinducibility of la antigens
on astrocytes with strain-specific susceptibility to experimental autoimmune
encephalomyelitis. Proceedings of the Naitronal Academy of science
1987;84:4219-4223.
8. Brahic, M. Stroop, W.R. and Baringer, J R. Theiler’s virus persists in glial
cells during demyelinating disease. Cell 1981 ,26,123-128.
9. Brewerton D.A. HLA-B27 and the inheritance of susceptibility to rheumatic
disease. Arthritis Rheum 1976;19:656-668.
10. Brinkman C.J.J. Nillesen, W.M. Hommes, O.R. Larners, K.J.M. DePauw,
B.E.J. and Delmotte P. Cell-mediated immunity in multiple sclerosis as
determined by sensitivity of different lymphocyte populations to various brain
tissue antigens. Ann Neurol. 1982;11-450.
11. Brown A. McFarlin, D.E and Raine C.S. Chronologic neuropathology
of
relapsing
experimental
allergic encephalomyelitis in the mouse.
Lab.lnvest 1982;46-171.
25. Rodriguez, M. and David, C.S. Demyelination induced by Theiler's
virus:
influence
of the H-2
haplotype.
Journal
of Immunology
1985;135:2145-2148.
26. Rodriguez M, Pease L.R. and David C.S. Immune-mediated injury of virus
infected oligodendrocytes. Immunology Today 7, 359-363.
27. Rosenthal A. Fujinami R.S. and Lampert P.W. Mechanisms of Theiler's
virus-induced demyelination in* nude
mice.
Laboratory Investigation
1986;54:515-522.
28. Schaumberg H.H. Spencer P.S. and Thomas P.K. Disorders ofperiheral
nerves. F.A. Davis Company, Philadelphia 1983;p27.
12. Chamorro M, Aubert C. and Brahic M. Demyelinating lesions due to virus
associated with ongoing central nervous system infection. Journal of
Virology 1986;57:992-997.
29. Schonberger. L.B. Hurwitz E.S. Katona p.Holman R.C and Bregman
D.J. Guillain-Barre syndrome:lts epidemiology and association with
influenza vaccination. Ann Neurol 1981 ;9 suppl 31,38.
13. Clatch R.J. Melvoid. R.W. Miller S.D and Upton H.L Theiler’s murine
encephalomyelitis virus (TMEV)-induced demyelinating disease in mice
is influenced by the H-2D region:correlation
with
TMEV-specific
delayed-type hypersensitivity. Journal of Immunology 1985;135:1408-1414.
30. Steiner I. and Abramsky O. Immunology of Guillain-Barre Syndrome.
Springer Seminars in Immunopathology 1985;8; 165-176.
14. Feldmann, M Regulation of HLA class II expression. Chapter in Autoimmu
nity and autoimmune disease. Ciba Foundation Symposium 1987;129:88-97.
15. Hafler D.A. Benjamin, D.S. Burks J. and Weiner, H.L Myelin basic protein
and proteolipid protein reactivity of brain and cerebrospinal fluid derived T cell
clones in multiple • sclerosis and postinfectious encephalitis. J.Immunol.
1987a;139,68.
31. Theiler M. Spontaneous encephalomyelitis of mice-a new virus disease.
Science 1934;80;122-123.
32. Todd I. Pujol-Borrell. R. Hammond LJ.Bottazzo G.f. and Feldmann, M.
Interferon-induces HLA-DR expression by thyroid epithelium. Clin Exp
Immunol 1985;61:265-273.
33. Toyka K.V. Drachman D.B. Prestronk A. and Kao I. Myasthenia gravis:
Passive transfer from man to mouse. Science 1975;190,397.
16. Hafler, D.A. DubyA.D.Lee S.J. Benjamin. D.Seidman, J. and Weiner H.L.
Oligoclonal T lymphocytes in the cerebrospinal fluid of patients with chronic
progressive multiple sclerosis. Neurology 1987;37,229.
34. Traugott U. Characterization and distribution of lymphocyte subpopula
tions in multiple sclerosis plaques versus autoimmune demyelination le
sions Springer Seminars in immunopathology 1985;8:71-96.
17. Jerne N.K. Towards a network theory of the immune system. Ann.
Immunol. Paris. 1974,125c,373.
35. Walker R, Cooke A, Bone A.J. Dean B.M. Vander Meide P, and Baird
J.C. Introduction of Class II antigens in vitro on pancreatic B cells isolated
from BB/E rats. Diabetologia 1986;29-749.
18. Kaplan M.H. and Meyersrian M. immunological Crossreaction between
Group a Streptococcal cells and human heart. Lancet 1962,1,706.
19. Upton H.L. Theiler's virus infection in mice: and unusual biphasic disease
process leading to demyelination. Infection and Immunity 1975,132:18211825.
20. Upton H.L. and Melvold R. Genetic analysis of susceptibility to Theiler's
virus-induced demyelinating disease in mice. Journal of Immunology
1984;132:1821-1825.
21.
LisaX R.P. Zweiman B. Whitaker J.N.
52
Spinal fluid basic protein
36. Waxman B.H. and Adams R.D. Allergic neuritis: Experimental disease of
rabbits induced by peripheral nervous tissue and adjuvants. J Exp Med
1955;102,213.
, 37. Welsh J.Avakian H. Cowling P et al., Ankylosing spondylitis, HLA-B 27
and Klebsiella. Brit. J.Exp.Path 1980;61:85-96.
38. Welsh C.J.R. Tonks P. Nash A.A and Blakemore W.F. The effect of L3t4
cell depletion on the pathogenesis of Theiler's murine encephalomyelitis virus
infection in CBA mice. Journal of General Virology 1987;68:1659-1667.
VOL III No. 2----
REVIEWS
St. John's Medical College Journal of Medicine
THERAPEUTIC ADVANCES IN PARKINSON’S DISEASE
K. RAY CHAUDHURI, R.J. ABBOTT
THERAPEUTIC ADVANCES IN PARKINSON’S DISEASE:
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, first described by James Parkinson (1817) as
the “Shaking palsy”. Charcot in the late 1800’s referred to
this disorder as Parkinson’s disease. It commmonly occurs
between 58 and 61 years age, but may present at any age
between 30 to 80 years.1
The clinical picture of PD is well recognized with resting
tremor being present in 60-70% patients as the initial symp
tom.1 Other features include bradykinesia, rigidity (usually
cogwheel), loss of arm swing, masked face, flexed posture,
loss of righting reflexes, and festinant gait often with start
hesitation
or freezing. Micrographia, hypophonia, and
dysarthria also occur and dementia along with depression are
observed fairly frequently.2
The prognosis of PD is difficult to predict individually. Hoehn
and Yahr’s review of 866 patients in 1967 revealed that 28%
of PD patients would be disabled or be dead by 5 years; the
figure rises to 61% by 10 years.3
THERAPEUTIC STRATEGIES IN PD:
Motor symptomatology in PD results mainly from degenera
tion of the zona compacta and loss of dopaminergic input to
the striatum. The basis of therapy in PD is replacing lost
dopaminergic influence.
Levodopa, introduced in 1961 by Birkmeyer and
Homykiewicz revolutionized the treatment of PD and has
improved the depressing prognostic picture. Though it does
not halt the progression of the disease, it has improved life
expectancy for the first 6 years of treatment. However Stern
reported after 12 years of continuous treatment the effect
of levodopa may be completely lost.4
Levodopa, initially caused frequent gastro-intestinal side
DR. K. RAY CHAUDHURI. M.R.C.P.
RESEARCH FELLOW AND HONORARY
REGISTRAR.
NATIONAL HOSPITAL OF NERVOUS DISEASES.
QUEEN SQUARE.
DR. R.J. ABBOTT. MD. M.R.C.P.
CONSUL TANT NEUROLOGIST
LEICESTER ROYAL INFIRMARY
LEICESTER.
JUNE
1990
effects, but it’s use in combination with a peripheral dopa
decarboxylase inhibitor (PDI) prevents this side effect. This
now is the standard treatment for symptomatic PD. Chronic
and continuous use of levodopa, however, may lead to
some well recognized side effects. These are loss of efficacy
of the drug, dyskinesias (diphasic,
peak-dose,
early
morning dystonia), psychiatric problems like confusion,
hallucination, psychosis, and fluctuations in motor perform
ances. Fluctuations in motor performances can be hyperki
netic, dystonic, or hypotonic. On-off oscillations, end-of-dose
failure and “wearing off" phenomenon are variations of the
above.5
The mechanisms leading to these side effects remain
unclear though pharmacokinetics of levodopa with alteration
of striatal levodopa bioavailability appear to be involved.6
Endogenous catecholamines with intrinsic neuronal rhythms
ortheir enzymes, tetrahydroisoquinolines, 3-o-methyl dopa
and excessive noradrenaline formation have all been
implicated.
6,7A9 Pharmacodynamics of levodopa with
alterations in postsynaptic dopamine receptors and natural
progression of PD appear to be involved as well.10
To avoid these problems new therapeutic strategies for
treatment of PD have been formulated and attempts have
been made to deliver levodopa to maintain a constant blood
level and improve the bioavailability. These include:
(A) Frequent small doses of L-dopa/PDI, often taken crushed
with fruit juice. This however is inconvenient and may lead
to more unpredictable responses.11
(B) Duodenal and intravenous infusion of levodopa has been
used with some success, but again, is of limited practical use;
also owing to its low pH, levodopa needs to be diluted in
large volumes of fluid.12
(G) Alteration in dietary protein has been tried with moderate
success.13
(D) Slow release form of L-dopa/PDI (Sinemet CR 4) has
been found to increase the “on” period in selected patients.14
OTHER TREATMENT STRATEGIES :
(A)
Dopamine agonists:
These act directly on the dopamine receptors (DR) without
requiring metabolism by the presynaptic nigrostriatal neu
rons. Kebabian and Caine subclassified DR’s into D1 and D2
subtypes. The important characteristics that differentiate
these are D1 stimulates adenylate cyclase (AC) and has a
high affinity for butyrophenones and substituted ben
53 —
St. John's Medical College Journal of Medicine
zamides.16 Animal studies have shown that D1 receptors
initiate locomotion and rotation along with biting and self
multilative behaviour.17 D2 stimulation leads to rotation and
locomotion along with most of the clinical effects of dopaminergicdrugs.17D2 receptor activity thus is principally related
to clinical response in PD. D1 receptor inhibits behavioural
tolerance to a D2 receptor antagonist by “overriding” the D2
antagonist signal.18 It may be that, D1 receptor activation
provides atonic background activation which may be equated
to level of arousal.19 A selective D1 antagonist may be able
to modulate L-dopa induced dyskinesias in PD.
The following DR agonists are in use :
Bromocriptine : This is an ergot derivative with a half life of
1.5 hours. It has a lysergic acid residue and a tricyclic
peptide, with lysergic acid probably being the pharmacologi
cally active moiety. It appears to have major activity at the
D2 receptors and is now widely used to treat PD. It has been
used alone to treat PD patients but more commonly as an
adjunct to L-dopa/PDI therapy. There have been sugges
tions that early combination therapy may prevent the onset
of fluctuations and have the same therapeutic efficacy as Ldopa/PDI.
Ergolides: These include pergolide, lisuride, lergotrile and
mesulergine.
Pergolide is a predominantly D2 receptor
agonist with a partial agonist activity at the DI receptors. It
improves motor performances in PD and has anti-parkin
sonian properties. The side effects are similar to
bromocriptine and include psychiatric problems, dyskinesias
and nausea/vomiting. Lisuride is another DR agonist and has
been used orally as well as via the intravenous and subcu
taneous routes. Continuous infusion of lisuride using a
portable battery operated infusion pump has been found to
be very effective in patients with major on-off oscilla
tions.20,21 However both lisuride and pergolide usage has
been associated with an unacceptable incidence of psycho
sis which makes its regular clinical use rather improbable.22
4-propyl-9-hydroxynaphthoxazine (PHNO):Thisisa power
ful D2 receptor agonist and is effective in improving tremor,
rigidity, and bradykinesia in PD patients in low doses.23
Application of PHNO to the skin reverses MPTP induced
parkinsonism. PHNO remains a drug under investigation and
is not in clinical use.
Apomorphine : Apomorphine, first described in 1882 by
Weil has been used in clinical practice mainly as an emetic
though it’s anti-parkinsonian properties were recognized by
Schwab et al.24,25 Cotzias gave oral apomorphine in large
doses to parkinsonian patients but noted pre-renal uraemia
in some patients leading to discontinuation of the drug. 26
Corsini suggested using domperidone to block its emetic
effects which are mediated via the dopaminergic area
postrema. Using this combination, Stibeet al. and our group
have found apomorphine to be extremely effective in
overcoming on-off swings in
PD patients, using a
54
subcutaneous infusion.2728 In addition
our observation
suggests that it may be of use in patients who are intolerent
to oral anti-parkinsonian medications, due to psychiatric
side effects.29 This may be due to a piperidine moiety which
is contained in the tetracyclic structure of apomorphine. It
has also been used via a prefilled penject system where
patients who can sense an impending off period can inject
themselves with apomorphine as a single stat dose. Our
group has noted improvement in tremor and recent studies
have also suggested the usefulness of apomorphine in PD
patients with voiding dysfunction and dysuria.30 An ‘apomor
phine lest’ similar to the lensilon test’ used for myasthenia
gravis, for diagnosis of difficult cases of PD has been
suggested. Side effects include lacrimation, drowsiness,
subcutaneous lumps and possibly weight gain. Thus apomor
phine has reappeared as an exciting prospect in the treat
ment of PD.
(B) Deprenyl (Selegiline) : This is a selective type B
monoamine oxidase (MAO) inhibitor. MAO forms one of the
major enzymatic pathway of catecholamine degradation;
type A oxidatively deaminating 5 HT and type B deami
nating phenylethylamine and benzylamine. MAO-B occurs
chiefly in the substantia nigra and corpus striatum where it’s
inhibition by selegiline leads to inhibition of nigrostriatal
dopamine breakdown. The principal therapeutic benefit is
to extend the action of L-dopa/PDI in patients with end of
dose deterioration.
In addition it has been suggested to
have a role in preventing the progression of PD.
This is because of the environmental theory which suggests
an agent like MPTP may get converted to the neurotoxin
MPP+by the MAO-B enzyme and thus it’s inhibition may
protect from the development of PD.31
(C) Anticholinergics
These include biperiden,
benzhexol, benzatropine etc. They are frequently used as
adjunct to L-dopa/PDI therapy and cause a slight reduction
in tremor, rigidity, cramps and aching discomforts. The
use of anticholinergics in elderly PD patients is perhaps
not recommended because of it’s implications on dementia.
(D) Amantadine : This is an antiviral drug which acts by
increasing synthesis and release of dopamine and diminish
ing re-uptake. It slightly enhances the action of levodopa and
side effects include oedema, postural hypotension and rarely
livedo reticularis. It may have an additive effect with the
anticholinergics.
(E) Tocopherol and Deprenyl: A recent double blind trial
with tocopherol and deprenyl has been set up by the
Parkinson study group in the USA. This selection is based
largely on the increasingly discussed role of environmental
neurotoxins and the potential role of oxidative mechanisms
within dopaminergic cells leading to cell death. The drugs
interfere with the oxidative mechanisms and therefore may
halt or slow progression of PD.
VOL HI No. 2----
St. John's Medical College Journal of Medicine
TRANSPLANTATION IN PARKINSON’S DISEASE:
Bjorklund and Stenevi in 1979 reported the implantation of
rat fetal dopaminergic neurones into chemically denervated
host rat striatum. There was subsequently metabolic and
physiological restoration of disordered function with active
sprouting of the graft.32 Lindvall etal. in 1987 carried out 4
stereotactic adrenal medullary autotransplantation in young,
non-demented, severely disabled PD patients. There was no
morbidity but there was also no long term benefit.33 Madrazo
et al from Mexico City reported impressive success in 2 young
PD patients treated with adrenal autotransplantation, using
an open microsurgical technique with implantation of adre
nal medulla into a preformed cavity in the head of the caudate
nucleus. 34 Centres in USA, China, Spain and Italy
subsequently carried out the Madrazo procedure. There
was substantial improvement with upto 57% reduction in
daily levodopa dose. But these encouraging results have
not been confirmed and Goetz et al from USA have reported
improvement in only 40% of patients with upto 5% mortality
rate.35
As adrenal auto transplantation proved disappointing a fetal
grafting programme was started in Sweden in 1985. A guide
line for use of human material was laid down after ethical
issues had been debated upon. 2 fetal transplantations were
carried out in 1987 and stereotactic implantation was used at
the putamen and caudate nucleus. Immunosuppression was
used and at 1 year there was no definite improvement either
clinically or on positron emission tomography using 6-L(18F)-flurodopa.36About75 implantations have been carried
out subsequently but the results have been disappointinng
or difficult to interpret owing to poor trial design. Transplan
tation in PD therefore may have a role in small minority of PD
patients with brittle responses and complicated disease.
Better and well designed human trials are needed before
transplantation can become a useful treatment in PD.
8. Ericsson AD.Potentiation of the L-dopa effect in man by the use of
catechol-o-methyl-transferase inhibitors. Journal of the Neurological Sci
ences 1971;14:193-197.
9. Sourkes TL. Possible new metabolites mediating actions of L-dopa.
Nature 1971;229:413-414.
10. Fahn S. "On-off phenomenon with levodopa therapy in parkinsonism.
Neurology, Minneapolis 1974;24:431-441.
11. Nutt JG. On-off phenomenon: relationship to levodopa pharmacoki
netics and pharmacodynamics. Ann. Neurol. 1987;22:535-540.
12. Kurlan R. Rubin AJ, Miller C, Rivera-Calimlim L, Clarke A, Shoulson I.
Duodenal delivery of levodopa for on-off fluctuations in
parkinsonism:
preliminary observations. Ann. Neurol. 1986;20:262-265.
13. Pincus JH. Barry KB. Influence of dietary protein on motor fluctuations in
Parkinson’s disease. Arch. Neurol. 1987;44:270-272.
14. Factor SA, Sanchez-Ramos JR. Ingenito AM, Weiner WJ. Efficacy of
Sinemet CR4 in subgroups of patients with Parkinson's disease. J.Neurol.
Neurosurg. Psychiatry. Submitted.
15. Kebabian JW, Caine DB. Multiple receptors for dopamine. Nature
1979;277:93-96.
16. Mackenzie RG, Kebabian JW. Dopamine receptors and signal transduc
tion. In. Hefti F.Weiner WJ. Eds. Progress in Parkinson Research. Plenum
Press. New York 1988;pp 53-60.
17. SeemanP, Grigoriadis D. Dopamine receptors in brain and periphery. J.
Neurochem. Int. 1987;1:1-25.
18. Creese I. New insights into the regulation of dopamine receptor
subtypes and their roles in behaviour. In. Hefti F, Weiner WJ. Eds. Progress
in Parkinson Research. Plenum Press. New York 1988;pp 1-10.
19. Hess EJ. Albers LJ. Le H. Creese I. Effects of chronic SCH 23390
treatment of the biochemical and behavioural properties of D1 and D2 recep
tors: Potentiated behavioural responses to a D2 dopamine agonist after
selective D1 dopamine receptor upregulation. J. Pharmacol. Exp. Ther.
1983;226:462-468.
20. Obeso JA, Luguin MR. Martine z-lage J. Usuride infusion pump: a
device for the treatment of motor fluctuations in Parkinson’s disease. Lancet
1986;1:467-470.
REFERENCES :
21. Ruggieri S. Stocchi F. Agnoli A. Usuride infusion pump for Parkinson’s
disease. Lancet 1986;2:348-349.
1. Factor AS. Weiner WJ.. The current clinical picture of Parkinson's
disease. In : Hefti F, Weiner WJ. Eds. Progress in Parkinson Research.
Plenum Press. New York 1988;pp1-10.
22. Critchley P, Grandas-Perez F, Quinn N. Coleman R. Parkes JD, Marsden
CD. Psychosis and the lisuride pump. Lancet 1987:2:349.
2. Brown RG, Marsden CD. How common is dementia in Parkinson's
disease? Lancet 1984;2:1262-1265.
3. Hoehn MD, Yahr MM. Parkinsonism : onset, progression and mortality.
Neurology 1967;17:427-422.
4. Stern G. Prognosis in Parkinson's disease. In : Marsden CD, Fahn S.
Eds. Movement disorders. Butterworths. London 1987;2:pp 91-98.
5. Hardie RJ. Lees AJ. Stern GM. On-off fluctuations in parkinson's
disease. Brain 1984;107:487-506.
6. Barbeau A. Long-term appraisal of levodopa
Minneapolis 1972;22:22-24.7
*
therapy. Neurology.
7. Birkmayer W, Riederer P, Youdim MBH, Unauer W. The potentiation
of tho anti-akinetic effect after L-dopa treatment by an inhibitor of MAO-B,
Deprenil. Journal of Neural transmission 1975;36:303-326.
JUNE
1990
23. Grandas-Perez FJ, Jenner PG, Nomoto M. et al. (+)-4-Propyl-9-hydroxynaphthoxazine in Parkinson's disease. Lancet 1986; 1:904.
24. Weill E. De 1’apomorphine dans certain troubles nerveux. Lyon Med.
1884;48:411-419.
25. Schwab RS. Amador LV, Levine JY. Apomorphine in Parkinson’s dis
ease. Trans. Am. Neurol. Assoc. 1951;76:251-253.
26. Cotzia GC. Papavassilou PS, Fehling c, Kaufman B. Mena I. Similarities
between neurological effects of L-dopa and of apomorphine. N. Eng. J. Med.
1970;282:31-33.
27. Stibe CMH, Lees AJ, Kempster PA, Stern GM. Subcutaneous
apomorphine in Parkinsonian on-off oscillations. Lancet 1988;1:403-406.
28. Ray-chaudhuri K, Critchley P, Abbott RJ. Pye IF, Millac PAH. Subcutane
ous apomorphine for on-off oscillations in Parkinson’s disease. Lancet
1.988;2:1260.
55 —
St. John's Medical College Journal of Medicine
29. Ray-chaudhuri K, Abbott RJ, Millac PAH. Subcutaneous apomorphine
for parkinsonian patients with psychiatric side-effects on oral treatment J.
Neurol. Neurosurg. Psychiatry. To be published.
30. Christmas TJ, Kempster PA, Chapple CRet al. Role of subcutaneous
apomorphine in parkinsonian voiding dysfunction. Lancet 1938;2:1451-1453.
31. Kopin IJ. Toxins and Parkinson's disease: MPTP parkinsonism in hu
mans and animals. Adv. Neurol. 1986;45:137-144.
32. Bjorklund A, Steevi U. Reconstruction of the nigral striatal dopamine
pathway by intracerebral nigral transplants. Brain Res 1979;177:555-560.
33.
Lindvall O, Backlund E-O, Farde L et al. Transplantation in parkinson's
56
disease: two cases of adrenal medullary grafts to the putamen. Ann. Neurol.
1987;22:457-468.
34. Madrazo I, Drucker-colin R, Diaz Vet al. Open microsurgical autograft of
adrenal medulla to the right caudate nucleus in two patients with intractable
Parkinson's disease. N. Eng. J. Med. 1987;316:831-834.
35. Goetz CG, OlanowCW, Koller WCet al. Multicentre study of autologous
adrenal medullary transplantation the corpus striatum into in patients with
advanced Parkinson's disease. N. Eng. J. Med. 1989;320:337-341.
36. Lindvall O, Rehncrona S, Brundin P et al. Human foetal dopamine
neurons grafted into the striatum in two patients with severe parkinson's
disease. Arch. Neurol. 1989,46:615-631.
----- VOL HI No. 2-----
CLINICAL PRACTICE
St. John's Medical College Journal of Medicine
THE PEAK EXPIRATORY FLOW RATE
INDIRA RAMIAH, GEETHA SUBRAMANIAM, OM PRAKASH
Assessment of lung functions has been in practice for several
years. Documentation of respiratory disability and its
categorisation into obstructive, restrictive and mixed varieties
is essential in the evaluation of respiratory diseases. Further,
simple tests used during followup visits will allow assessment
of progress of disease as well as response to various modes
of therapy. While clinical spirometry is the most widely used
test of lung function, the peak expiratory flow rate (PEFR)
is extensively employed by clinicians in initial evaluation of
patients as well as in follow up of the course of disease. This
is particularily of relevance to two very common problems in
chest practice, namely asthma and chronic bronchitis. This
article reviews some of the essential aspects of the PEFR
measurement in the light of current literature as well as our own
experience at the chest clinic at St. Martha’s hospital,
Bangalore.
The basis of the PEFR was established by Wright of the
pneumoconiosis research unit in England in 1959. In a paper
in the British Medical Journal, he described the experiences
with a peak flow meter and established that it is a useful and
reliable instrument. The PEFR has, over the years, become an
established parameter.
and also has peak inspiratory flow rate measuring capabil
ity.
All these instruments are useful and none has any special
advantage. In most cases, the PEFR is measured in
the longitudinal assessment of a given paitent and hence
minor inconsistencies between instruments does not
matter. The important thing is for the clinician to become fa
miliar with one meter and use it frequently.
THE MEASUREMENT:
The patient is instructed to take a deep breath and hold the
mouth piece firmly between his lips and blow out as hard as
he can.
As this is an effort dependent test, the patient’s understand
ing and cooperation are crucial. The PEFR is then noted
in liter/minute or per second as the case may be. Two or
three efforts can be measured and the best PEFR recorded.
The meters are calibrated on a scale ranging from a low of
60 liters/minuteto the maximum of 650(Assess) or800 (mini
Wrights) liters. The patient’s value is then expressed as
a percentage of the predicted PEFR for the age and sex.
THE PEAK FLOW METER
In the initial years, the larger dial type of peak flow meter was
in use. In 1972, the more portable peak flow gauge came into
use. Currently, the mini-Wright peak flow meter is widely used
as it is cheaper and more portable. Wright and Gregg have
established that the mini-Wright meter values closely corre
late with the older Wright’s meter. This instument has a
cylindrical structure with a diaphragm which moves away in
response to the expiratory effort and is brought back by a
spring. The diaphragm carries with it a marker which stops at
the peak flow value and has to be brought back to origin
manually.
The Vitalograph pulmonary monitor is another simple and
portable meter, essentially similar in design to the mini-Wright
meter. The popular American model, the Assess peak flow
meter, is very similar except that the cylinder is vertical in
disposition. Recently, an Indian model, the Pink City Flow
meter has been introduced; this is a very cheap instrument
OM PRAKASH - HEAD OF DEPT. OF MEDICINE
INDIRA RAMIAH - PHYSICIAN
GEETHA SUBRAMANIAM - PHYSICIAN
REPRINT REQUESTS:
OM PRAKASH
HEAD OF DEPT OF MEDICINE
ST. MARTHAS HOSPITAL
BANGALORE - 560 001.
JUNE
1990
PEFR : THE PHYSIOLOGIC BASIS
What does the PEFR signify? It measures the maximal
expiratory flow at a given instant of time. The adequacy of
the test thus depends on the patient’s optimal performance
of a forced and sudden expiration. The PEFR is a function
of several factors which have to be considered. Firstly, the
PEFR is related to the adequacy of the airway caliber. In
other words, with increasing airway obstruction, the PEFR
falls. Secondly, the test being dependent on forceful
contraction of the respiratory muscles - particularity the
diaphragms, any functional or major anatomic anomaly of
the diaphragm may result in a lowered PEFR. Forinstance,
limited excursion of the diaphragms in gross ascites or
obesity may lower the PEFR. Unilateral paralysis of the
diaphragm can result in a somewhat reduced PEFR.
Likewise, kyphoscoliosis results in a diminished PEFR by
interfering with the function of the diaphragm and the intercostals. Thirdly, any cause of severe restriction of the vital
capacity may result in the reduction of PEFR, while mild
degrees of restriction will not do so. Lastly, any disease
state characterised by impaired neuromuscular transmis
sion (as in Guillain Barre Syndrome) or muscular weakness
(as in myopathies) will obviously result in lowered PEFR.
Thus in interpreting the result of the PEFR in a patient, the
clinician has to ascertain that none of the confounding
factors are operative. Conversely, if a given subject has a
significantly reduced PEFR, a cause for this finding, be
57 —
St. John's Medical College Journal of Medicine
it related to intrinsic lung disability or another factor has to
be looked for.
CLINICAL APPLICATIONS
A.
Bronchial asthma
1) Diagnosis: Central to asthma is the demonstration
of
reversable airways obstruction. In this context, the
PEFR
can be measured and repeated after inhaling
bronchodialator aerosol; if over 15% of increase in PEFR
over the baseline
can be shown, reversible airways
obstruction can be
diagnosed with confidence. Often,
patients present with no
obvious clinical forms of airways
obstruction; yet the PEFR
can be low due to subclinical
airway obstruction. In such cases, the objective measure
is useful.
2) Nocturnal asthma : The asthmatic state generally
worsens at night. In some cases, the airway function may
be normal du ring day, making the clinician suspect the ve
racity of the
history. It is well known, however, that many
asthmatics
wheeze only at night. In these instances,
the simple
expedient of measurement of the PEFR at
night when the patient is symptomatic will help in diagnosis.
The dramatic fall in the PEFR at night or in the early hours
of the morning establishes the diagnosis.
3) Excercise induced asthma : While most asthmatics
tend to
wheeze on sufficient excercise, the magnitude
of this
phenomenon can be documented by PEFR. A
small segment of
asthmatic population have asthma
exclusively on exertion and these cases can be diagnosed
with confidence with the
help of pre and post-exercise
PEFR studies.
4) Routine Management : During formulation of a
therapeutic programme as well as in follow up visits, routine
PEFR checks are very valuable. The behaviour of the PEFR
allows optimal alterations in the regimen so that a suitable
long term programme can be arrived at. This aspect has
great import in asthmatics in general; even more important is
the role of objective measurement of airway function in
asthmatics who either tend to minimise or deny the severity
of their disease or those who exaggerate their symptoms.
5) Ruling out asthma: Often one enocunters patients who
have emotional distress presenting as ‘dyspnea’. In these
cases, the asthmatic state can be ruled out by frequent
measurement of PEFR. Normal nocturnal PEFR and lack
of fall after exercise will argue emphatically against the
presence of asthma.
6) Prevention of acute severe asthma: The role of PEFR
in chronic asthmatics has to be emphasised. A low PEFR
should immediately alert the physician into aggressive ther
apy with short course of steroids and other measures. Many
a case of asthma can be prevented from getting critical by the
simple means of routine PEFR assessment.
7)
has to be supported by objective measurements as the
disease is characterised by a varying natural course as well
as by difficulty in evaluating the degree of airways obstruc
tion by clinical means alone. Further, evaluation of drugs,
clinical trials comparing two medications, assessment of
efficacy of a given medication such as cromolyn sodium in
blocking exercise induced asthma etc need objective
parameters of measuring the asthmatic state.
B.
Chronic Bronchitis
Chronic bronchitis and emphysema, collectively called
COPD, are common entities in our communities. They
cause considerable morbidity and mortality. Diagnosis and
some
degree
of quantification of the diffuse airways
obstruction in COPD can be made with the aid of PEFR. It
is useful in this context as a screening device so that more
elaborate tests of lung function like spirometry and lung
volumes can be ordered in the presence of a reduced PEFR.
Repeated measurement of PEFR may allow differentiation
between asthma and COPD; the former is characterised by
labile PEFR with fluctuations over days as well as diurnal
variations. The later is generally noted to have a fixed and low
PEFR. Also, asthmatics tend to show reversibility with bronchodialotors while COPD subjects show poor reversibility.
C.
As a screening device
Many studies have shown that in general practice, the routine
use of the PEFR is helpful in detection of many cases of
unsuspected respiratory disability. PEFR is also useful in
preliminary analysis of subjects at increased risk to develop
chronic airflow limitation as in some occupations.
In conclusion, it can be stated that the peak flow meter is an
invaluable, simple device in chest practice as well as a
screening test in general practice, it is particularly useful in
diseases with chronic airway obstruction both in diagnosis
as well as in management.
SUGGESTED READING:
1. Bronchodialator therapy; The basis of asthma and chronic obstructive
airways disease management. Ed: TJH Clark. AIDS Press Ltd., USA. 1984.
Predicted Peak Flow Rates; South Indian Norms.
Age Range
Sex
15-19
20-24
25-34
35-44
45-54
>55
Males
530
553
558
511
470
451
Females
400
394
363
359
328
282
Clinical research: Any clinical research work on asthma
58
VOL III No. 2----
ADVANCES IN TECHNIQUE
St. John's Medical College Journal of Medicine
LARYNGEAL MASK
R. RAJENDRAN
Neuromuscular block not required for intubation.
This has been described by leading researchers as a quan
tum leap in the management of anaesthetised patient.
Developed and extensively tested in the UK this new airway
provides an effective alternative to the endotracheal tube
in many situations.
6. Removal of the tube can be done at the end of su rgery when
the patient has regained all reflexes. Well tolerated till the
time the patient is fully awake.
DESCRIPTION
7.
No post operative sore throat.
The laryngeal mask consists of an inflatable silicone ring
attached diagonally to a flexible tube. The ring forms an oval
mask which fills the space around and behind the larynx
achieving a low pressure seal betweenthe tube and trachea
without penetration of the larynx.
8.
IPPV is possible at low inflation pressures
The laryngeal mask is designed for blind insertion into the
lower pharynx. Slight bulging of the neck indicates approxi
mate correct placement where upon gentle inflation of the
mask aligns the aperture in the mask opposite the laryngeal
opening. If tracheal access is required it is possible to pass
a small endotracheal tube or flexible fibreoptic scope directly
through the tube of the laryngeal mask into the trachea.
Using the intravent
STERILISATION
The mask is made from high quality medical silicone. It can,
therefore, be autoclaved without damage and reused several
times.
5.
9. Enables bronchial inspection with a fibreoptic broncho
scope via the tube of the laryngeal mask.
10.
Can be life saving even in unskilled hands.
1. Inflate the cuff of the sterilised laryngeal mask then deflate
completely pressing the hollow side down on a clean flat
surface so that the cuff folds away from the aperture.
2.
Lubricate the back of the cuff throughly before insertion.
3.
Anaesthesia must be deep enough for insertion.
4. Extend the neck and insert the cuff with the aperture facing
the tongue taking care that the tip lies flat against the roof of
the mouth.
5. Grip shaft near the outer end with the index finger over the
aperture and push down with a single confident movement.
Size coding
One - Neonatal upto 6.5 Kg
Two - 6.5 Kg to 25 Kg
Three - 25 Kg to a small adult
Four - Normal to large adult
BENEFITS
6. Stop pushing when resistance is felt as the tip of the cuff
reaches the upper oesophageal sphincter.
7. Now immediately inflate the cuff without holding the tube.
This will permit the laryngeal mask to position itself
correctly.
1. Occupies a position intermediate between face mask
and endotracheal tube, more secure than a face mask and
less invasive than an endotracheal tube.
8.
Connect the ‘gas’ supply.
9.
Insert the bite block and tape the mask into place.
2. Hands-free control of the airway. No jaw manipulation
required.
REMOVAL
3.
Easy to insert even if the airway is awkward.
4.
Overcomes difficult/impossible intubation problems
It is essential to leave the patient completely undisturbed until
protective reflexes have fully returned. Look for the onset of
swallowing. Then deflate the cuff completely prior to removal.
RAJENDRAN R. MD
ASST. PROF. OF ANAESTHESIOLOGY
STANLEY MEDICAL COLLEGE
MADRAS
PRECAUTIONS
CORRESPONDENCE TO
96, NORTH, JAGANATHAN NAGAR,
VILLIVAKKAM
MADRAS - 600 049 ’
Laryngeal spasm may occur if the patient becomes too
lightly anaesthetised during surgical stimulation or if the
bronchial secretions
irritate the vocal cords during
emergence from anaesthesia.
JUNE
1990
Laryngeal mask does not prevent regurgitation so normally
it should be used only on fasting patients.
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