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MED J MALAYSIA VOL 63 NO 5 DECEMBER 2008 EDITORIAL

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MED J MALAYSIA VOL 63 NO 5 DECEMBER 2008 EDITORIAL Powered By Docstoc
					MED J MALAYSIA VOL 63 NO 5 DECEMBER 2008

EDITORIAL
INTRODUCING A NEW SERIES OF INVITED REVIEW ARTICLES
K G Lim, FRCS
Malaysian Medical Association, 4th Floor, MMA House, 124 Jalan Pahang,
53000 Kuala Lumpur

In a number of fields of medical research, Malaysian investigators
have made notable scientific contributions, which perhaps for their
importance, have been published in international scientific journals.
These findings, scattered in various specialist medical journals,
would have found their audience among specialists of similar
interests.   However, these findings ought to be of interest to a
different audience on account of their place of origin.    Being about
Malaysian patients, it is only fitting that these findings should have
a Malaysian audience.

The Medical Journal of Malaysia hopes to be a forum for the local
publication of important findings of our Malaysian medical researchers
whose work have gone international – and perhaps escaped local
attention. The Medical Journal of Malaysia actually has an open door
for publication of relevant abstracts from other journals.     But, we
noticed that nobody actually knocks on that door!    We have therefore
begun to invite eminent Malaysian medical scientists who become
experts in their field of study and had their work published elsewhere
to write review articles for our local audience.       We ask them to
review the topic of their investigation with special mention of their
contribution to it. We introduce the first of these series of reviews
in this issue of the journal.

CT Tan and HT Chong have, together with    several co workers, published
over twenty papers on multiple sclerosis   in Malaysia. In fact, it was
CT Tan through a post mortem study who      established the existence of
multiple sclerosis in this region beyond   doubt.

We look forward to more reviews like this in the future.       We have
several writers in the pipeline but readers can suggest topics and
writers to the Editorial Board to consider inviting them. It will be
the prerogative of the Board to decide on the suitability of the
subject and the author. However, do remember that if you come across
an article in an international journal or have written such an article
that has contents relevant to Malaysia, that the option of writing an
abstract of relevant papers is a door that is still open.
JOINT EDITORIAL
PLAGIARISM : A JOINT STATEMENT FROM THE SINGAPORE MEDICAL JOURNAL AND
THE MEDICAL JOURNAL OF MALAYSIA
W C G Peh, FRCR*, J Arokiasamy, MPH**
*Editor, Singapore Medical Journal, 2 College Road, Singapore 169608,
**Editorial Advisor, Medical Journal of Malaysia, MMA House, 124 Jalan
Pahang, 53000 Kuala Lumpur, Malaysia

Both the Singapore Medical Journal (SMJ) and the Medical Journal of
Malaysia (MJM) have recently encountered a number of submissions of
plagiarized work to our respective journals.   This utterly dishonest
practice is universally deplored by editors of all medical and
scientific journals. As it is imperative that journal readers should
be able to trust that what they are reading is original, we feel very
strongly that punitive measures should be applied to authors found
guilty of plagiarism, in order to discourage this undesirable
practice. The academic career of an author found guilty of plagiarism
may potentially be destroyed, in addition to reduction in the
credibility of the plagiarist’s co authors, his or her professional
colleagues, department and institution.

The World Association of Medical Editors (WAME) defines plagiarism as
the use of others’ published and unpublished ideas or words (or other
intellectual   property)   without    attribution or  permission,  and
presenting them as new and original rather than derived from an
existing source.    To put it simply, this crime refers to stealing
someone else’s work or ideas, and passing it off as one’s own. For a
researcher, this form of scientific misconduct represents fraud of the
worst order.    WAME further states that “the intent and effect of
plagiarism is to mislead the reader as to the contributions of the
plagiarizer”. This applies whether the ideas or words are taken from
abstracts, research grant applications, institutional review board
applications,   or   unpublished   or   published manuscripts  in  any
publication format, whether print or electronic.     The boundaries of
what constitutes plagiarism are therefore not limited just to journal
articles or other published work, but includes someone else’s ideas or
words in all forms, so long as intellectual theft occurs.

There are, however, grey areas such as paraphrasing versus quoting,
and self plagiarism. Paraphrasing refers to the practice of restating
a text or passage giving the meaning in another form; in short, a
rewording of the original sentence or group of sentences.        Some
authors paraphrase in an attempt to overcome the increasingly common
practice of “cut and paste” research.   As a rough guide, using more
than 5% of other articles in their words may be regarded as
plagiarism. Where a paraphrase is unable to convey the full message
from the original paper or if there is a danger of misinterpretation,
the exact words can be quoted using quotation marks. The problem in
quoting is that, if too liberally used, it may reflect a lack of
original ideas or analytical interpretation, and may paradoxically
encourage the tendency to plagiarise.   Currently, there still remain
divergent views about what constitutes plagiarism versus appropriate
paraphrasing. For example, in investigating cases of plagiarism, the
US Office of Research Integrity (ORI)”does not pursue the limited use
of identical or nearly identical phrases which describe a commonly
used methodology or previous research because ORI does not consider
such use as substantially misleading to the reader or of great
significance.

WAME defines self plagiarism as the practice of an author using
portions of their previous writings on the same topic in another of
their publications, without specifically citing it formally in quotes.
There is no consensus as to whether this is a form of scientific
misconduct, or how many of one’s own words one can “steal from
oneself” before it truly constitutes “plagiarism”.    This is probably
the reason why self plagiarism is not regarded in the same light as
plagiarism of the ideas and words of other individuals. However, some
take the opposing viewpoint that duplication publication is but a
continuum of self plagiarism, and leads to undesirable “salami”
science.    The act of re using substantial portions of already
published text without proper referencing is ethically problematic, as
it violates the implicit reader writer contract that what the reader
is reading is original and new.         As most authors would have
transferred the ownership of his or her work to the publisher, any
self plagiarism would therefore technically violate the copyright that
has previously been assigned to the publisher.

Plagiarism may be detected at various stages of manuscript processing
by the editorial officer and reviewers, and after publication, by
other readers including the victim(s) of plagiarism.       Editors can
monitor their own journals for plagiarized articles by using the
“related article” feature of PubMed.      Google/Google Scholar covers
databases such as documents on servers of numerous academic
institutions.    The effectiveness of this and other online search
services in detecting plagiarism depends on the coverage of the
underlying databases that the submitted manuscript is being checked
against,   and  the   uniqueness  of   the   selected  sequence/phrase.
Experienced editors or writers will be able to pick up various tell
tale signs of plagiarisms such as unevenness of writing style,
unexplained switching between UK and US spelling in the same document,
and disproportionately small number of references in relation to text.

If plagiarism is attempted or occurs, authors should expect editorial
action to be taken. The editor, sometimes with the assistance of his
editorial   team,  will  conduct   initial  fact   finding,  including
correspondence with the authors for their explanations.        If the
inquiry concludes that plagiarism had indeed occurred and if the
manuscript is still being processed, it will be promptly rejected. If
the article has already been published, then a notice of plagiarism
may be published.   The offending paper will be formally withdrawn or
retracted from the scientific literature, and the indexing authorities
(e.g. National Library of Medicine) informed.      A formal letter of
reprimand will be sent to the author, copied to the relevant heads of
the author’s department and institution, together with the evidence
collected by the journal.    For the SMJ, copies of this letter will
also be sent to the editors of the MJM and the Annals Academy of
Medicine Singapore. The author will be further informed that the SMJ
and MJM will no longer be interested in considering his or her future
submissions. We believe that these actions reflect the seriousness of
the offence. This policy is in line with the recommendations of WAME,
the International Committee of Medical Journal Editors, and the
Committee on Publication Ethics (COPE). COPE has developed excellent
flowcharts that provide algorithms for editors who have queries
related to publication misconduct.



INVITED REVIEW ARTICLE
A REVIEW OF MULTIPLE SCLEROSIS WITH ASIAN PERSPECTIVE
H T Chang, FRCP, C T Tan, FRCP
Division of Neurology, Department of Medicine, University of Malaya,
50603 Kuala Lumpur, Neurology Laboratory, University Malaya Medical
Centre, 59100 Kuala Lumpur, Malaysia

SUMMARY
Multiple sclerosis, although a rare disease in Asia, often presents
significant diagnostic challenges to clinicians. There has been rapid
advancement in the understanding of the underlying genetic influence,
pathophysiology, investigation and treatment recently.    This Paper
reviewed the latest development of various aspects of the disease and
examined the differences between the manifestations of Asian and
Western patients.      The implications of these differences to
investigation and treatment were also touched upon.

KEY WORDS : Multiple Sclerosis, Neuromyelitis Optica, Asian


INTRODUCTION
Multiple sclerosis is an idiopathic, autoimmune, demyelinating disease
affecting the central nervous system. It is commonest among women in
their 20s to 40s, and it is the commonest non traumatic cause of
disability among young people in Western countries. The prevalence of
multiple sclerosis varies mainly with gender, ethnicity and latitude,
especially the latitude of the place where the patient spends the
first 15 years or so of life. Regions with high prevalence (> 30/105)
include Western Europe, North America, Southeast Australia and the
whites of New Zealand. Regions with medium prevalence (between 5/105
to   29/105)  include   Eastern   Europe,  southern   shores  of   the
Mediterranean, Mexico, South Africa, southern parts of South America
and the rest of Australia.     The rest of Asia, Africa and northern
South America have low prevalence (< 5/105). The illness is commoner
among whites and the female to male ratio varies from 2:1 to 3.8:1.
The prevalence of multiple sclerosis was 1.39/105 in Shanghai, China, 4
and 7.7/105 in Japan.

In Malaysia, even as late as the 1980s, the disease was thought not to
exist here. The first detailed description of multiple sclerosis, and
thus the proof of its existence in Malaysia, was published in 1988.
Since then, it was found that its prevalence, computed in comparison
to that of amyotrophic lateral sclerosis, which has a stable worldwide
prevalence, is about 2 to 3/105, and it is commoner among the Chinese
than the Malays. It was thus estimated that there are currently about
500-750 patients in Malaysia.     However, a recent survey conducted
among the Ministry of Health hospitals in Malaysia suggested that
perhaps the difference in prevalence rates among the races was less
pronounced than previously thought (personal communication : Dr
Shanthi V, Hospital Kuala Lumpur).    Recent study also suggested that
the prevalence of the disease, especially the classical, Western form,
is on the rise at least in northeast Asia.

AETIOLOGY
The actual cause of multiple sclerosis is not known and is probably
multifactorial as both environmental and genetic factors have been
proven to be important.     The concordance rates are nearly 30% in
monozygotic twins and 2% in siblings or dizygotic twins, compared to
the highest population prevalence of 0.1-0.2%, Since 1972, association
with HLA-DRB1 gene on chromosome 6p21 has been established and it is
still the single most important genetic locus found to be associated
with multiple sclerosis. Meta analyses of large genetic studies have
suggested additional minor loci on 5p, 17q and 19q.      Recent genome
wide analysis of 12,000 subjects for single nucleotide polymorphism
markers indicated minor involvement of two additional genes, IL2RA on
chromosome 10p15, which encodes the alpha subunit of interleukin 2
receptor (CD25) and IL7RA on chromosome 5p13, which encodes the alpha
subunit of interleukin 7 receptor.   These findings suggest that cell
mediated immunity plays a key role in the immunopathogenesis of
multiple sclerosis.

Latitudinal variation in the prevalence of multiple sclerosis and
migration studies suggested that environmental factors are as, if not
more, important as genetic factors.      A dramatic increase in the
incidence of multiple sclerosis in the Faroe Island after the
deployment of British garrison during the Second World War suggested
that infective agents may be the causative or precipitating factor of
the disease. Recent studies have implicated Epstein Barr virus as one
such possible culprits. Serum vitamin D levels had been shown to have
a significant negative correlation with the risk of multiple
sclerosis; and vitamin D supplement was also shown to be associated
with lower risk of the disease, although the exact mechanism of how
vitamin D supplement reduces the risk of multiple sclerosis is not
known.
PATHOLOGY AND PATHOPHYSIOLOGY
The pathological hallmark of multiple sclerosis is the focal, well
delineated demyelinating plaques, with myelin destruction on a
background    of    inflammation    and   later,     glial   scarring.
Macroscopically, the plaques appear to be sharply demarcated within
the white matter tracts of the brainstem, spinal cord, within the
periventricular regions and the optic nerves.       Within the active
plaques, the inflammatory cells consist mainly of T lymphocytes with
extensive macrophages and microglial activation and a small number of
B lymphocytes and plasma cells. Axonal transaction, however, is found
to be present extensively in active and chronic active lesions even in
patients who were diagnosed recently and in normal appearing white
matter.

The inflammation in these plaques is associated with an up regulation
of a variety of cytokines and chemokines, such as interleukin 2, α
interferon and α tumour necrosis factors.     Other active participants
in this process include CD8+ T cells and antibodies to myelin
proteins, such as myelin oligodendrocytes glycoprotein (MOG) and
myelin basic protein (MBP). After the inflammatory process subsides,
remyelination   and  gliosis   follows.     A   systematic  review   of
demyelinating plaques suggested four immunopathological patterns :

Pattern I : T cells/macrophages mediated demyelination
Pattern II : Antibody/complement mediated demyelination
Pattern III : Oligodendrocyte dystrophy with myelin dysregulation and
oligodendrocytes apoptosis
Pattern IV : Primary oligodendrocytes degeneration.

Although the pattern of demyelination tend to be the same in multiple
lesions in the same patients at any one time, the pattern varies from
patient to patient, and it does not correlate well with the clinical
course, except for pattern IV, which has only been identified in
patients with primary progressive disease.

Increasingly, neurodegeneration is thought to play an important role
early in the course of the illness, and inflammation may not be the
initiating trigger in lesion formation, suggesting that pattern III
lesions may be the evidence suggesting that pattern III lesions may be
the precursors to the typical pattern I and/or II plaques.     Current
evidence suggests that oligodendrocyte apoptosis occurs before the
setting in of inflammation, and is likely to be the trigger of
inflammation. The cause of oligodendrocyte apoptosis is yet unknown,
though some authors have suggested that viruses such as the human
retrovirus, HERV-W, may be the cause.

CLINICAL FEATURES
The mean age of onset is 31 years. The commonest presenting symptoms
in classical multiple sclerosis include sensory disturbance in the
limbs (33%), unilateral visual loss (16%), motor deficits (14%) and
diplopia (7%).   The sensory disturbance often involves one limb then
the other, however, it may vary from ascending numbness mimicking
Guillian   Barre   syndrome  to  radicular   pain,  dysaesthesiae   and
paraesthesiae.   Another less common sensory symptom is Lhermitte’s
phenomenon, which is described as an electric shock like sensation
traveling down the back to the legs upon flexion of the neck. Other
symptoms   include    acute  motor   deficits,   diplopia,   cerebellar
disturbance and cranial nerve palsy.          In Asia, the commonest
presenting symptoms are myelitis (33%), optic neuritis (29%),
brainstem (14%) and cerebellar symptoms (4%).

In a joint Asian study, 45% of patients had at least a clinical
episode of acute transverse myelitis. The onset often progresses over
a few days.    The initial complaint is numbness and weakness of the
lower limbs, progressing to incontinence, loss of proprioception and
walking difficulty.    Examination showed variable loss of strength.
The tone and reflexes may be normal initially, but the limbs would
become hypertonia and hyperreflexic over the next few days.        The
cervical cord is the commonest site of involvement, followed by the
thoracic cord. Initial attacks of myelitis tended to recover rapidly
and completely. However, with recurrent attacks, the recovery tended
to become less complete.    Severe weakness and loss of proprioception
herald poor recovery.    During recovery, a significant proportion of
patients developed paroxysmal tonic spasm; a frequent, intermittent,
painful motor spasm of the affected limbs which may spread from one
muscle group to another. The spasm is often over within minutes, but
may recur numerous times in a day.            The spasm responds to
carbamazepine, and is good indicator that the myelopathy is of
demyelinating etiology. Regionally, 28% of the patient complained of
paroxysmal tonic spasm during the course of their illness.

Optic neuritis is also very common presenting symptom, occurs in about
15-35% of patients in the Western countries. In a joint Asian study,
48% of patients had at least a clinical episode of optic neuritis.
Bilateral optic neuritis is also not rare and subclinical optic
neuropathy is relatively common in Malaysia. The presenting complaint
is sudden onset of vision loss or blurring, often, though not always,
accompanied by pain.   Pupillary reflex may be spared in mild cases.
In severe cases, the involvement of the afferent pathway of the
pupillary reflex arc results in the Marcus Gunn pupil. Upon recovery,
the patients most often had impairment of contrast sensitivity, and
less often visual field and colour vision defect.      Therefore, even
those without visual field defect may complain of loss of colour
brilliance upon recovery.      The visual field defect was highly
variable, ranging from central scotoma to hemianopia. Like myelitis,
initial attacks tend to recover rapidly and completely, though with
recurrent attacks, blindness is not uncommon.

About 80% of patients presented initially with a relapsing remitting
course; however, after a number of years, most of the patients entered
the secondary progressive phase, during which the neurological
deficits progressed relentlessly even during remission of relapses.
This occurs in 12% of the patients during 5 years, 40% after 10 years
and 66% after 25 years. The other 10-20% of patients have continual
progression of symptoms independent of relapses from the onset of the
disease; those with relapse are termed progressive relapsing multiple
sclerosis, and those without are termed primary progressive multiple
sclerosis.   Progressive disease is less common in Asia; in a recent
survey, in which the mean duration of illness was 9.3 years, 79% of
patients remained in the relapsing remitting phase and only 7% of
patients progressed to secondary progressive phase. Eleven percent of
these patients had relapsing progressive disease and 3% had primary
progressive disease.

DIAGNOSIS AND INVESTIGATIONAL FINDINGS
The diagnosis of multiple sclerosis hinges on demonstrating that the
attacks   of  presumed   central  nervous  system  demyelination  are
disseminated in space and time and there is no better explanation for
these attacks.   The differential diagnoses of multiple sclerosis are
varied and many, including multiple stroke, multiple metastases and
central   nervous   system   lymphoma.     Clinically,   evidence  of
dissemination in time can be obtained by taking a detailed history,
and that of dissemination in space by showing that on neurological
examination the signs are localized to more than one site in the
central nervous system.    When the clinical history could not prove
that the attacks were disseminated in time, serial MRI showing
occurrence of new T2 or gadolinium enhanced lesions is sufficient to
prove dissemination in time. Similarly, when neurological examination
does not show evidence of multiple lesions, the presence of
subclinical MRI lesions is sufficient to prove dissemination in space
as in modified McDonald criteria.

Therefore, among all the paraclinical tests, MRI is the most
important.   Its sensitivity approaches 95% in Western patients, and
specific lesions are best seen in T2 or FLAIR weighted images.    The
typical findings are multiple small, round or ovoid, discrete lesions
in the juxtacortical, periventricular, callosal or pericallosal
regions. Acute lesions are often enhanced with gadolinium.

The typical cerebrospinal fluid findings include the presence of
oligoclonal bands, normal or mildly elevated protein and normal cell
counts, though in Asian patients, only 27% of patients were found to
have positive oligoclonal bands and lymphocytic pleocytosis is not
rare.

In Asian patients, though the MRI findings were found to be largely
similar to those of the Western patients in terms of lesion
distribution and appearance, there were significant differences as
well. Asian patients had fewer brain lesions and longer, more severe
spinal cord lesions and rare involvement of the cerebellum.   The MRI
findings were also less likely to fulfill McDonald’s criteria on
dissemination in space.   Therefore, we recently proposed that future
diagnostic criteria should take these into account by reducing the
number of MRI brain lesion necessary for diagnosis, inclusion of long
spinal cord lesions, or cord lesions involving the entire cross
sectional area, as consistent with MS plaques.        It was further
proposed that relapses restricted to clearly separate lesions of the
spinal cord be accepted as sufficient to demonstrate dissemination in
space.

Table I : Symptomatic Treatment

          Symptoms                           Treatment
Fatigue                  Fatigue management programme
                         Amantadine
                         Modafinil
                         Calcium channel blockers
Spastic bladder          Pelvic floor exercises
                         Clean intermittent self catheterization
                         Oxybutynin
                         Tolterodene
Nocturia                 Intranasal desmopressin (DDAVP)
Detrusor hyperreflexia   Intravesical capsaicin
Constipation             High fiber diet
                         Osmotic    laxative    such   as   lactulose    &
                         polyethylene glycol
                         Senna
                         Biscodyl
                         Erectile dysfunction Sildanefil
                         Intracorporeal alprostadil
Spasticity               Physiotherapy
                         Avoidance of noxious stimuli (such as poor
                         posture, fecal impaction, ingrown toenail,
                         urinary tract infection)
                         Baclofen (10-80 mg daily in 3 doses)
                         Tizanidine (6-32 mg daily in 3 doses)
                         Dantrolene
                         Memantine
                         Viagabatrin
                         Cannabis
                         Botulinum toxin injection for focal spasticity
                         Paroxysmal tonic spasm Carbamazepine
                         Phenytoin
                         Lamotrigine
                         Gabapentin
                         Chronic     pain     Trancutaneous     electrical
                         stimulation
                         Amitriptylene
                         Eye movement disturbances Prisms
                         Baclofen
                         Gabapentin
                         Isoniazid
                         Memantine
Vertigo                  Physiotherapy
                         Cinnarizine
Dysphagia                Percutaneous     endoscopic    gastrotomy    tube
                         feeding
NEUROMYELITIS OPTICA,   OPTIC   SPINAL   MULTIPLE   SCLEROSIS   AND   MULTIPLE
SCLEROSIS IN ASIANS

Since the 1970’s it was recognized that MS patients in Asia have
different clinical features compared to those in North America and
Europe.   The main differences are lower prevalence, rare familial
occurrence, higher female to male ratio, more severe optic nerve and
spinal cord attacks, fewer brain and cerebellar lesions, higher
proportion of optic nerve and spinal attacks, lower proportion of
progressive disease and lower incidence of positive oligoclonal bands.
Those patients in Asia who have clinical relapses (though not
necessarily radiological or pathological lesions) limited to the optic
nerves and the spinal cord are said to have optic spinal disease or
neuromyelitis optica in that the former is a polyphasic or relapsing
condition while the latter monophasic.

Pathological, NMO lesions showed necrosis and cavitation associated
with the demyelinating plaques.    A series of reports in the 1990’s
also found that the MRI of patients with NMO showed a paucity of brain
lesions, but the spinal cord lesions were longer than the usual MS
lesions.     Unfortunately,  these   reports   did   not  differentiate
monophasic from polyphasic disease. Recently, it was found that both
NMO and OSMS were associated with an autoantibody directed against the
water channel, the anti aquaporin 4 antibody.     The autoantibody test
was found to be 73% sensitive and 91% specific for NMO and 58%
sensitive and 100% specific for OSMS.    It was therefore claimed that
OSMS is NMO but not MS.

However, a joint American Japanese pathological study on multiple
sclerosis   did   not  find   any   substantial  differences  in   the
histopathology of multiple sclerosis lesions in Northern American and
Japanese patients with MS.    What was noted to be different was the
distribution of the lesions. A recent MRI studies of MS patients in
the Asia Pacific region showed a significant proportion of those with
OSMS fulfilled the MRI dissemination in space diagnostic criteria for
multiple sclerosis. The paucity of brain lesions and the presence of
long spinal cord lesions were not specific for OSMS but were seen in
Asian patients with classical MS.          Recent reports from Asia
contradicted some of the initial findings on anti aquaporin 4 antibody
– the sensivity was only 5.6-27.1% and up to 25% of patients having
other neurological conditions (such as idiopathic transverse myelitis)
were positive.    More importantly, the autoantibody was found to be
associated with the severity and frequency of relapses rather than
with NMO or OSMS – the autoantibody was more likely to be positive
patients who fulfill MRI criteria for MS, who had long spinal cord
regardless of the underlying diagnosis and who had more frequent
relapses.   The nature of NMO and OSMS, the pathogenesis of these
diseases and their association with MS are still topics of intense
debate currently.
TREATMENT
The management of patients with multiple sclerosis can be divided into
the   management  of   acute  relapses,   disease  modifying  therapy,
symptomatic treatment and rehabilitation.

Except for minor sensory relapses, the treatment of acute relapses is
intravenous methylprednisolone at doses of 1,000 mg daily for 3 to 5
days.   Tapering doses of oral prednisolone has not been shown to
improve results, and may increase the risk of side effects.      It is
important to remember that paroxysmal symptoms such as Uhthoff
phenomenon may mimic relapse, and these should not be treated with
high dose steroid.     Moreover, steroid only hastens the speed of
recovery and has not been shown to improve on the eventual disability.
Since paroxysmal symptoms seldom last longer than a few hours and that
actual relapse lasts more than 24 hours (but does not continue to
deteriorate for more than 30 days), it is therefore worthwhile to
observe the patient for a day or two when the cause of neurological
deterioration is uncertain.   In patients with disabling relapses and
who do not respond to high dose steroid, plasmapheresis has been shown
to be effective in improving outcomes in two randomized, double blind,
controlled trials.

The definitive treatment of relapsing remitting disease that reduces
relapse rate, MRI burden of disease and disease progression are the β-
interferon 1a and 1b are mostly given as subcutaneous injection weekly
or every other day.    Generally, they reduce relapse rate by about a
third on intention to treat analysis, reduce lesion areas on MRI and
delay progression to sustained disability by up to 18 months.      The
effect was sustained even after 10 years.    There is a dose response
relationship, in that high dose β-interferon has been shown to be more
effective than low dose or less frequent dose regime.       Glatiramer
acetate, on the other hand, has only been proven to reduce relapse
rate and the burden of disease on MRI, but not the progression of the
disease.    The main limiting factor to the widespread use of β-
interferon locally is the prohibitive cost.

There are recent recommendations that β-interferon treatment should be
started as early as possible, even as soon as the first attack if the
patient has MRI changes.       However, these trials used slightly
different MRI criteria. This is further confounded in Asia where the
overall prevalence of multiple sclerosis is very low, the MRI changes
are not as florid, and the conversion rate of a single isolated
demyelinating event to multiple sclerosis is not known.

Older immunosuppressants have not been found to be as useful.
Sulfasalazine and cladribine do not reduce relapse rate, though
mitoxantrone,  azathioprine   and  intravenous   immunoglobulin could
possibly do.      None of these, perhaps with the exception of
mitoxantrone, delay the progression to disability. Other newer agents
that have been proven useful include the monoclonal antibodies,
natalizumab, alemtuzumab, daclizumab and rituximab, as well as other
immunosuppressant such as fingolimod, monthly pulse methylprednisolone
or intravenous immunoglobulin.

The treatment of progressive disease is more controversial.         β-
interferon, monthly intravenous immunoglobulin and cladribine were not
shown to delay disease progression. Mitoxantrone and possibly monthly
pulse methylprednisolone, methotrexate and cyclophosphamide could
stabilize disease progression, but the toxicity of these compounds
limits their long term use.        Future therapy for relapsing and
progressive disease may focus on neuroprotective agents or neuronal
stem cell transplantation.

Given that current therapy is not able to cure or totally arrest the
progression of disabilities, symptomatic and rehabilitation therapy
forms an important aspect of the management of multiple sclerosis.
Many of the symptoms are amenable to pharmaceutical and surgical
intervention, while others are better managed with rehabilitation
(Table I).

PROGNOSIS
The progression of multiple sclerosis is well studied.      The median
time to reach irreversible disability milestones, such as Disability
Scale scores of 4 (limited walking ability, but without aid or rest
for more than 500m), 6 (ability to walk with unilateral support no
more than 100m without rest) and 7 (ability to walk no more than 100m
with aid), which is 8, 20 and 30 years respectively, is consistent in
many studies worldwide. Important prognostic factors include gender,
age of disease onset, characteristics of relapses and the occurrence
of progressive disease in the first years of the disease. Younger age
of onset, female gender, monosymptomatic onset (such as optic
neuritis), complete recovery from the attacks, a long interval between
the first year has been consistently associated with a better
prognosis in the past.    Recent studies of large patient databases,
however, are beginning to shed new light on this.       In the London,
Ontario study, it was found that patients with primary progressive
disease, single attack followed by disease progression sometimes later
and   patients  with   secondary  progressive   disease   reached  the
progressive stage at the same age (38.6, 40.9 and 39.2 years
respectively), though the onset ages were different (38.6, 33.3 and
29.8 years respectively).   Similarly Confavreux et al found that in
the Lyon, France, database, the initial course of disease and the
number of relapses did not substantially influence the age at
disability milestone – specifically, the number of relapses and the
initial course of relapsing or progressive disease did not influence
the interval of reaching DSS of 7 from 4 or 6, though the disease
duration was longer in those with relapsing disease.        These data
suggest that degeneration characterizes the later phase of the disease
and the progression of disability continues even in the absence of
relapses.   Along the same vein, it has been proposed that perhaps
different phenotype and course of multiple sclerosis (relapsing and
progressive) are perhaps the same disease manifested at different
phases.
The natural history of multiple sclerosis in Asia is less well
studied.   In Malaysia, 54% of patients with myelopathy without a
definite cause went on to develop multiple sclerosis after 5.5 years
of follow with the female sex as the only risk factor. In those with
established MS, the frequent attacks of optic neuritis and myelitis
impacts negatively on the patients’ prognosis, hence it was not
surprising that Asian patients reached the same level of disability 5
to 10 years earlier than their Western counterparts. It was also not
surprising to find that the number of relapses did not affect the
level of disability; but on logistic regression analyses, progressive
course of illness, a history of transverse myelitis, incomplete
recovery from the first attack and abnormal somatosensory evoked
potential study were associated with more severe disability.      Long
term disability study similar to those from London, Ontario and Lyon,
France, will be invaluable in determining the nature of various types
of multiple sclerosis in Asia, including that of optic spinal multiple
sclerosis.

CONCLUSION
Over the last twenty years, an explosion of knowledge has impacted
every aspect of our understanding of multiple sclerosis.    The genome
wide survey, the findings of early axonal injury, the importance of
neuronal degeneration as elucidated by both pathological and long term
clinical studies and the early occurrence of oligodendrocyte apoptosis
as the trigger of inflammation had revolutionized our understanding of
multiple sclerosis.   The advent of MRI has given us a sharp tool in
diagnosis; and that of cytokines and monoclonal antibodies has for the
first time enabled us to alter the course of the illness without much
side effect. The future looks even brighter with a host of drug going
through the phases of trials which will add to our armamentarium of
treatment. Finally, the understanding of the pathophysiology and the
availability of sensitive diagnostic imaging tools will not only
enable us to prognosticate better, but also allow us to better assess
the effectiveness and efficiency of new treatment.
ORIGINAL ARTICLES
PSYCHOLOGICAL DISTRESS, QUALITY OF LIFE AND COPING IN CANCER PATIENTS : A
PROSPECTIVE STUDY
A Suthahar, MMed (Psych)*, K Gurpreet, MPH**, D Ambigga, MMed (Fam
Med)*, S Dhachayani, MA (Clinical Psychology)***, I Fuad, FRCR***, T
Maniam, MPM***, C B Osman, MMed (Psych)*, O Ainsah, PhD*
*Faculty of Medicine, Universiti Teknologi MARA, 40450 Shah Alam,
Selangor,   **Institute  for   Public   Health,  Ministry   of   Health,
***Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000 Kuala
Lumpur, Malaysia

Summary
We present the results and conclusions of an observational prospective
cohort design study using self administered questionnaires to
determine correlation between psychosocial factors and cancer outcome
among 80 consecutive newly diagnosed treatment naïve cancer subjects
who were being referred to the Oncology Clinic, Hospital Universiti
Kebangsaan Malaysia.    Subjects were recruited over a period of 43
weeks from October 2000 till July 2001.    Follow up assessments were
carried out at 6 months and 12 to 26 months later. The prediction of
survival time was performed by the Cox Regression Analysis method with
adjustments for biological and psychosocial risk factors.       It was
noted that depression (p = 0.001), stage 4 cancer disease (p = 0.016),
neurological (p = 0.032), gastrointestinal tract (p = 0.04), head and
neck (p = 0.011), gynaecological (p = 0.005) and bone and soft tissue
(p   =  0.030)   malignancies   were  independent   and  statistically
significant prognostic factor of survival during the study period. It
was further shown that depressed patients were found to have almost
four fold greater risk of dying than non depressed patients and
patients with stage 4 cancer illness have a fivefold greater risk of
dying than patients with stage 1 disease.       Furthermore, based on
tumour types, subjects with neurological, gynaecological, head and
neck, bone and soft tissue and gastro intestinal tract malignancies
were found to have approximately thirty six, twenty five, twenty two,
sixteen and seven fold greater risk of dying respectively when
compared to subjects with genitourinary cancers.    This study further
affirms the need for health care providers to be aware of the
psychological aspects of the cancer patient and provide appropriate
therapy so as to ensure that this group of individuals would have
enhanced survival rates.

Key Words :     Depression, Survival, Cancer Patients, Cox Regression
Analysis
PAEDIATRIC AIRWAY RECONSTRUCTION : A PRELIMINARY STUDY
Z Amin, MMed (ORL-HNS)*, S A H Suzina, MMed (ORL-HNS)**
*Department of Otorhinolaryngology-Head & Neck Surgery, Kulliyyah of
Medicine, International Islamic University Malaysia, Jalan Hospital
Campus, 25100 Kuantan, Pahang, **School of Medical Sciences, Hospital
Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia

Summary
To   set  the   foundation  for   developing  a  centre   for   airway
reconstruction, we performed a retrospective database review of
patients operated at a tertiary care university hospital.     Over the
past 3 year period from 2004 onwards, five paediatric cases of airway
reconstruction procedures were performed. All cases had a two stages
laryngotracheal reconstruction (TSLTR) for laryngotracheal stenosis
(LTS). All patients were children below 15 years and the mean age was
9 years.   Only one patient had a Grade IV Myer-Cotton stenosis, the
rest all had Grade III stenosis. Three out of four of the Grade III
stenosis patients were successfully decannulated within one year, the
other one died of causes unrelated to LTS. The grave IV patient was
still under follow up and surgery was done only recently. This Paper
highlights the complexity of managing LTS in the paediatric age group
and recommends the use of LTR with rib graft as a choice for the
management of LTS.

Key Words :     Paediatric,      Laryngotracheal       Reconstruction,
Laryngotracheal Stenosis


HEAD INJURY WITH TEMPORAL BONE FRACTURE : ONE YEAR REVIEW OF CASE
INCIDENCE, CAUSES, CLINICAL FEATURES AND OUTCOME
Z Amin, MMed, ORL-HNS, R Sayuti, MMed, ORL-HNS, A Kahairi, MMed, ORL-
HNS, W Islah, MS ORL-HNS, R Ahmad, MS, ORL-HNS
Department of Otorhinolaryngology-Head and Neck Surgery, Kulliyyah of
Medicine, International Islamic University Malaysia, Jalan Hospital,
25100 Kuantan, Pahang, Malaysia

Summary
To investigate the case incidence, causes, clinical profile and
outcome of temporal bone fracture complicating head trauma. A 1 year
(2005) retrospective study of head injury patients presented to the
Emergency Department, Hospital Tengku Ampuan Afzan, Kuantan, Pahang,
Malaysia. Gender distribution, cause of injury, radiological findings
and otorhinolaryngological clinical presentations were analyzed.    Of
1,309 patients, 61 patients were diagnosed to have temporal bone
fracture (4.7%).    Majority of cases were caused by motor vehicle
accident (85.9%) and were predominantly male (88.5%).        The right
temporal bone was more frequently fractured (62.3%).      Most (88.5%)
were petro mastoid fractures.     Sixty seven percent of the petrous
fractures were longitudinal type.       Clinical presentations mostly
reported were blood rhinorrhea (36%)and blood otorrhea (32.7%). Other
clinical presentations were hearing loss (9.8%), cranial nerve palsy
(8.2%), cerebrospinal fluid oto-rhinorrhea (8.2%) and labyrinth
concussion (6.5%). Four out of five cranial nerve palsies were facial
nerve. Out of the 61 cases, 16 (26.2%) had no clinical presentation
at the time of Emergency Department consultation.    Thirteen (21.3%)
died due to severe head injury. The case incidence of temporal bone
fracture in head injury patients in our centre is 4.7%.     The petro
mastoid type fracture predominates.     Proper early diagnosis and
management minimize complications.

Key Words :     Temporal Bone Fracture, Head Injury, Petro Mastoid


ENDOSCOPIC CAUTERIZATION OF THE SPHENOPALATINE ARTERY IN PERSISTENT
EPISTAXIS
S Harvinder, MMed (ORL HNS), S Rosalind, MMed (ORL HNS), S Gurdeep, MS
(HNORL)
Department of ENT, Hospital Ipoh, Jalan Hospital, 30990 Ipoh, Perak,
Malaysia

Summary
The management of epistaxis remains to be a challenging problem for
most ENT surgeon especially posterior epistaxis.       Most cases are
managed by placement of posterior nasal packs or balloons and failure
leads to more invasive techniques, involving ligation of the internal
maxillary artery. The above management is associated with significant
patient   complication  and   morbidity.     Endoscopic   ligation  or
cauterization of the sphenopalatine artery has emerged as a viable and
minimally invasive alternative.        We have performed endoscopic
cauterization of nine sphenopalatine arteries in eight patients with
no further episodes of epistaxis and complications, with an average
follow up of 25 months. The mean age of the patients was 52.75 years.
Fifty percent of the patients had a history of hypertension.

Key Words :     Endoscopic, Epistaxis, Sphenopalatine Artery


MTHFR C677T POLYMORPHISM AS A RISK FACTOR OF NEURAL TUBE DEFECTS IN
MALAYS : A CASE CONTROL STUDY
A R Hayati, DCP*, A I Zainal, MPath*, G C Tan, MPath*, L C Ong, MRCP*,
T B Khoo, MRCP**
*Departments of Pathology and Paediatrics, Faculty of Medicine,
Universiti Kebangsaan Malaysia, **Department of Paediatrics, Hospital
Kuala Lumpur, Malaysia

Summary
Major congenital malformations occur in about 3% of newborns. Several
studies   have    suggested   that   homozygosity   for    the  C677T
methylenetetrahydrofolate reductase (MTHFR) variant is a potential
risk factor for neural tube defects (NTDs). It has been hypothesized
that the maternal folic acid supplementation prevents NTDs by
partially correcting reduced MTHFR activity associated with the
variant form of the enzyme.   This association has not been found in
some ethnic groups.     In this study, we attempted to assess the
association between NTDs and MTHFR C677T in the Malaysian Malay
population. Results show that MTHFR C677T genotype was absent in both
patient and control groups.

Key Words :     Genetics,   Malay   Ethnic,   MTHFR   C677T,   Neural   Tube
Defects, Polymorphism


END TIDAL TO ARTERIAL CARBON DIOXIDE PARTIAL PRESSURE DIFFERENCE
DURING CRANIOTOMY IN ANAESTHETISED PATIENTS
J Husaini, Y C Choy
Department of Anaesthesiology and Intensive Care, Faculty of Medicine,
Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak,
56000 Cheras, Kuala Lumpur, Malaysia

Summary
This study to evaluate the relationship between end tidal carbon
dioxide pressure (ETCO2) and arterial partial pressure of carbon
dioxide (PaCO2) included 35 patients between the ages of 18 and 65
years, ASA grade 1 and 2, who had elective craniotomies. Measurements
of PaCO2 and ETCO2 were taken simultaneously : 1) 10 minutes after
induction of general anaesthesia; 2) after cranium opening prior to
dural incision, 3) start of dural closure.       There was significant
correlation between ETCO2 and PaCO2 (correlation coefficient : 0.571,
0.559 and 0.629 respectively). The mean (SD) difference for PaCO2 and
ETCO2 were : 3.84 (2.13), 4.85 (5.78) and 3.91 (2.33) mmHg
respectively.     Although there was agreement, the bias is of
significant clinical importance.    In conclusion, we find that ETCO2
consistently underestimated the value of PaCO2 during craniotomy.

Key Words :     End Tidal Carbon Dioxide Pressure, Arterial Partial
Pressure of Carbon Dioxide, Craniotomy


HYPOSPADIAS FROM THE PERSPECTIVE OF A SINGLE SURGEON PRACTICE IN
MALAYSIA
B H Yeap, FRCS, N Mohan, FRCS
Department of Paediatric Surgery, Hospital Alor Star, Alor Star,
Kedah, Malaysia

Summary
The last decade has witnessed an alarming increase in the worldwide
incidence of hypospadias.    For non hypospadiologists, the surgical
correction of hypospadias will be increasingly demanding. This Paper
aims to evaluate the effectiveness of a treatment strategy devised by
a single surgeon practice in Malaysia to tackle this anticipated surge
of caseload. Over a period exceeding eight years, 254 boys underwent
corrective hypospadias surgery by a single paediatric surgeon at Alor
Star Hospital, Malaysia.    Patient demographics, racial distribution
and meatal location were among the data collected retrospectively.
The various types of corrective procedure employed, their outcome as
well as complications were evaluated.       Distal type of hypospadias
dominated this series.    There was an explainable peculiarity in the
age distribution of hypospadias.       For all types of repair, the
complication rate was 33% consisting mainly of urethrocutaneous
fistula (18%) and meatal stenosis (9%).          Complication rate for
tubularised incised plate (TIP) urethroplasty, the commonest technique
of   repair  was   30%,   mainly  from    meatal   stenosis  (15%) and
urethrocutaneous fistula (13%).     Univariate analysis revealed that
proximal hypospadias, repairs done during the initial four years of
study and utilization of repair other than TIP to be adverse risk
factors. Tubularised incised plate urethroplasty was appropriate for
almost all types of hypospadias.     For the remainder, the two stage
repair is satisfactorily employed. This study from a primary referral
centre also dispelled the notion that proximal hypospadias predominate
in this region. The versatility and reliability of TIP urethroplasty
lends itself readily in tackling primary and repeat hypospadias
surgery within a single surgeon practice.

Key Words :     Hypospadias, Tubularised Incised Plate Urethroplasty,
Fistula, Stenosis


RETROSPECTIVE REVIEW OF CORNEAL ULCERS IN IPOH HOSPITAL
M R Kursiah, M Ophthal, F Mohd Sharif, M Ophthal, P Balaravi, DORCPLS
Department of Ophthalmology, Hospital Ipoh, Perak, Malaysia

Summary
This study was a retrospective study on corneal ulcer of one year
period in Hospital Ipoh. A total of 28 cases were studied. Among the
risk factors identified were foreign body on cornea, trauma, contact
lens, vernal keratoconjunctivitis and surgical complication.       The
nature of this disease which was severe and slow healing caused
prolonged   hospital   admission.      Identification   of   causative
microorganism by corneal scraping help in the treatment and management
of this condition.

Key Words :     Corneal Ulcer, Cornea Scraping, Contact Lens Induced
Corneal Ulcer
A CASE CONTROL STUDY ON FACTORS THAT INFLUENCE DEPRESSION AMONG THE
ELDERLY IN KUALA LUMPUR HOSPITAL AND UNIVERSITI KEBANGSAAN MALAYSIA
HOSPITAL
O Salimah, MPH*, M A Rahmah, PhD**, R Rosdinom, MMed (Psych)***, S
Shamsul Azhar, MPH**
*Family Health Development Division, Ministry of Health, Putrajaya,
**Department of Community Health, ***Department of Community Health,
***Department of Psychiatry, Universiti Kebangsaan Malaysia Medical
Centre, Jalan Yaacob Latiff, 56000 Cheras, Kuala Lumpur, Malaysia

Summary
Depressive illness is common among the aged population.        A case
control study was conducted, focusing on risk factors influencing
depression among the elderly.       This study involved 130 elderly
patients diagnosed to have depressive illness from the psychiatric
clinics of Kuala Lumpur Hospital (HKL) and Universiti Kebangsaan
Malaysia Hospital (HUKM). Another group of 130 elderly patients with
no history of depressive illness were recruited from the medical
specialist clinics.   The majority of cases were female (75.4%), aged
60-74 years (92.3%) and from Chinese ethnic group (59.2%). Non Malay
elderly has three times risk (AOR 2.537, 95% CI 1.439-4.471) of
suffering the depressive illness compared to the Malay elderly, the
elderly with chronic health problems are more likely to be depressed
compared to those who do not suffer from any chronic illness (p trend
< 0.001).    Other risk factors identified were family history of
depression with four times risk (AOR 4.225, 95% CI 2.017-8.848) and
lower social support with eight times risk (AOR 7.949, 95% CI 2.588-
24.417).   Social support is not only important in encouraging the
elderly to practice healthy lifestyle but proven to influence the risk
of getting depression among them. Hence, it is very crucial that the
elderly is given total attention, respect and love from all parties to
ensure prosperity and meaningfulness in life.

Key Words :     Depression, Risk Factors, Social     Support,   Chronic
Disease, Elderly, Malaysia, Case Control Study


GASTROINTESTINAL MANIFESTATIONS OF DENGUE INFECTION IN ADULTS
E T Ooi, MRCP*, S Ganesananthan, FRCP*, R Anil, MRCP*, F Y Kwok,
MBBS*, M Sinniah, FRCPath**
*Medical Department, **Virology Unit, Kuala Lumpur General Hospital,
Jalan Pahang, 50586 Kuala Lumpur, Malaysia

Summary
This is a retrospective study of the gastrointestinal symptoms, signs
and laboratory parameters in adult dengue patients admitted to Kuala
Lumpur Hospital from 1 December 2004 to 31 December 2004. Clinical and
laboratory parameters that may predict the need for intensive care
were investigated.   Six hundred sixty six with dengue infection were
identified.    Patients were stratified into those who required
intensive care and those who were managed in non high dependency
wards.   Serum alanine aminotransaminase (ALT) levels were normal in
22.8% of patients and 5.9% of patients had acute fulminant hepatitis.
More patients with dengue haemorrhagic fever (DHF) had elevated ALT
levels as compared to patients with classic dengue fever (DF) (p =
0.012).   Patients with DF had a statistically significant lower mean
ALT level as compared to patients with DHF.       Abdominal pain (p =
0.001) and tenderness (p < 0.001), gastrointestinal bleed (p < 0.001),
jaundice (p < 0.001), hepatomegaly (p < 0.001) and ascites (P < 0.001)
were predictors of need for intensive care.          We conclude that
gastrointestinal manifestations are very common in dengue patients.
Presence of abdominal pain and tenderness, gastrointestinal bleed,
jaundice, hepatomegaly and ascites can be used to triage patients
requiring intensive care.

Key Words :      Dengue,   Gastrointestinal   Manifestations,   Hepatitis,
Intensive Care

				
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