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Multiple Sclerosis
Version 1 Final
EBM – Multiple Sclerosis
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1 Final
19 March 2007
Signed off by MSCMT
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1 March 2007
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1d (draft)
22 January 2007
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1c (draft)
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Introduction
Definition
Multiple Sclerosis is a chronic inflammatory disease of the central nervous system
characterised by plaques of demyelination at sites throughout the CNS. Diagnosis is
clinical, and requires evidence of lesions that are separated in time and space, and
the exclusion of other inflammatory, structural or hereditary conditions that might
give a similar clinical picture.
The disease takes three main forms: -
Relapsing and remitting - characterised by episodes of neurological dysfunction
interspersed with periods of stability.
Primary Progressive - in which progressive neurological disability occurs from the
outset.
Secondary Progressive - in which progressive neurological disability occurs in the
later stages of the disease. [1]
In 90% of people, early disease is relapsing/ remitting. Most develop secondary
progressive disease, usually 6-10 years after onset. In 10% the disease is
progressive from the outset however, as detailed later, the rate of progression
appears similar and functional loss at any specific age is a factor of years with
disease rather than actual age. [8] In the majority of patients life expectancy is not
greatly affected.
Aetiology and Incidence
The cause is unknown but an immunological abnormality is suspected. One
postulated cause is infection by a latent virus (possibly by a human herpes virus or
retrovirus) in which virus activation and expression trigger a secondary immune
response. An increased familial incidence and association with certain HLA allotypes
suggest genetic susceptibility.
Environment may be a factor. MS is more common in temperate climates (1/2000)
than in the tropics (1/10,000). It has been linked to the geographical area where the
individual spent their first 15 years. Relocation after age 15 years does not alter the
risk. In Europe and North America MS is the most common cause of neurological
disability in young adults.
Age of onset is broad peaking between 20 and 40 years. [2]
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Diagnosis
Symptoms and Signs
Physical
The disease is characterised by various symptoms and signs of CNS dysfunction,
with remissions and recurring exacerbations. First presentations are usually
monosymptomatic. The most common early presenting symptoms are :-
Parasthesiae in one or more extremities, in the trunk, or on one side of
the face.
weakness or clumsiness of a leg or hand
visual disturbances, e.g., partial blindness and pain in one eye
(retrobulbar optic neuritis), dimness of vision, or scotomas.
Other early symptoms are:
ocular palsy resulting in double vision (diplopia)
transient weakness of one or more extremities
slight stiffness or unusual fatiguability of a limb
minor gait disturbances
difficulty with bladder control
vertigo
mild emotional disturbances
These symptoms indicate scattered C.N.S. involvement and often occur months or
years before the disease is recognized. Excess heat (e.g., warm weather, a hot
bath, and a fever) may accentuate symptoms and signs.
Mental
Apathy, lack of judgment, or inattention may occur.
Other cognitive difficulties may manifest with problems in the ability to
pay attention, learn and remember information, solve problems, and use
language to express ideas. It is now estimated that 50% of people may
have some degree of cognitive impairment rising to 80% if the most
severe cases are included.
Emotional lability is common and may suggest an incorrect initial
impression of hysteria. Euphoria occurs in some patients.
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Reactive depression.
Sudden weeping or forced laughter (concomitants of pseudobulbar
palsy) indicates that corticobulbar pathways of emotional control are
affected.
Convulsive seizures seldom occur.
Severe changes (e.g., mania or dementia) can occur late in the disease.
Scanning speech (slow enunciation with a tendency to hesitate at the
beginning of a word or syllable) is common in advanced disease and
often associated with cerebellar involvement.
Aphasia is rare.
Cranial Nerves
Optic neuritis is a broad term expressing inflammation, degeneration, or
demyelination of the optic nerve. It includes:
papillitis or anterior optic neuritis - the intraocular portion of the nerve is
affected, and the optic disc is swollen
retrobulbar neuritis - optic neuritis in which the disc is not swollen
neuroretinitis - optic disc and adjacent temporal retina are affected
The majority of patients under the age of 45 years recover normal visual acuity
within 2 months. Older patients recover less well and there may be evidence of optic
atrophy. .Patients with MS may have recurrent episodes of optic neuritis. With each
subsequent episode there is less recovery and there will be a degree of long term
visual impairment.
Optic atrophy with temporal pallor can be seen on fundoscopy, and is associated
with optic neuritis.
Internuclear ophthalmoplegia – this is weakness or paralysis of eye movements
caused by damage to nerve fibres that give rise to cranial nerves III, IV and VI,
which results in painless visual disturbance and diplopia on lateral gaze. There is
nystagmus in the abducting eye.
Nystagmus is a common finding and may be due to cerebellar or vestibular nucleus
damage.
Other evidence of cranial nerve involvement is uncommon, and when present, is
usually due to brain stem injury in the area of the cranial nerve nuclei.
Deafness is rare, but vertigo is not.
Unilateral facial numbness or pain (resembling trigeminal neuralgia) occurs
occasionally, as does hemifacial palsy or spasm.
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Motor nerves
Deep reflexes (e.g., knee and ankle jerks) are generally increased.
Babinski's sign (upgoing plantar response) and clonus (sustained
muscle contraction) may be present.
Often, the patient complains of unilateral symptoms, but examination
elicits signs of bilateral corticospinal tract involvement.
Intention tremor due to cerebellar lesions is common, and continued
purposeful effort accentuates it. The motion is ataxic, shaky, irregular,
tremulous, and ineffective.
Static tremor may occur. It is especially obvious when the head is
unsupported.
Muscular weakness and spasticity from corticospinal damage produce a
stiff, imbalanced gait. Later, a combination of spasticity and cerebellar
ataxia may become totally disabling. Cerebral lesions may result in
hemiplegia, sometimes the presenting symptom.
Painful flexor spasms in response to sensory stimuli (e.g., bedclothes)
may occur in late stages.
One pattern of disease includes acute optic neuritis, sometimes
bilateral, with demyelination of the cervical or thoracic spinal cord (optic
neuromyelitis), producing visual loss and paraparesis.
Charcot's triad (nystagmus, intention tremor, and scanning speech) is a
common cerebellar manifestation in advanced disease.
Mild dysarthria may result from cerebellar damage, disturbance of
cortical control, or injury to the bulbar nuclei.
Sensory nerves
Complete loss of any form of cutaneous sensation is rare
Parasthesiae, numbness, and blunting of sensation (e.g., reduced pain
or temperature sense, disturbances of vibratory or position sense) may
occur and are often localized, e.g., to the hands or legs. Objective
changes are fleeting and are often elicited only with thorough testing. A
range of painful sensory disturbances (e.g., burning, electrical, or
paroxysmal pain) can occur, especially with spinal cord demyelination.
Autonomic nerves
Urinary urgency or hesitancy, partial retention of urine, or slight incontinence and
constipation are common when the spinal cord is affected, as are erectile
dysfunction in men and genital anaesthesia in women.
Urinary and faecal incontinence may occur in advanced disease.
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Differential Diagnoses
The following is a list of conditions that may share some overlap with multiple
sclerosis:
AIDS.
Amytrophic lateral sclerosis
A rare fatal progressive degenerative disease that affects pyramidal motor neurons,
usually begins in middle age, and is characterized especially by increasing and
spreading muscular weakness. (also known as Lou Gehrig's disease.)
Abnormalities of the spine or skull base.
Arthritis of the cervical spine.
Basilar Invagination (upward bulging of the occipital condyles)
CNS tumours, abscess or other mass lesions. Guillain-Barre syndrome
A polyneuritis of unknown cause characterized especially by muscle weakness and
paralysis.
Hereditary ataxias Any of a group of inherited neurodegenerative disorders that are characterized by
cerebellar dysfunction manifested especially by progressive ataxia.
Lyme disease
Pernicious Anaemia
Ruptured intervertebral disc
Small cerebral infarctions
Tertiary Syphilis
Syringomyelia A chronic progressive disease of the spinal cord associated with sensory
disturbances, muscle atrophy, and spasticity.
Systemic Lupus Erythematosus An inflammatory connective tissue disease of unknown cause that can involve the
CNS.
Transverse Myelitis
Inflammation of the spinal cord or of the bone marrow.
Vascular malformations of the brain or spinal cord
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Investigations
No single investigation can reliably diagnose MS – diagnosis is a combination of
clinical symptoms and signs supported by laboratory testing and brain imaging.
Typical cases can usually be diagnosed confidently on clinical grounds. The
diagnosis can be suspected after a first attack, especially in a young patient with
sensory, motor or visual disturbance. Later, a history of remissions and
exacerbations and clinical evidence of C.N.S. lesions disseminated in more than one
area are highly suggestive. Other possibilities must be considered.
Magnetic Resonance Imaging (MRI), the most sensitive diagnostic imaging
technique, may show plaques. It may also detect treatable non-demyelinating
lesions at the junction of the spinal cord and medulla (e.g., subarachnoid cyst,
foramen magnum tumours) that occasionally cause a variable and fluctuating
spectrum of motor and sensory symptoms, mimicking MS. Gadolinium-contrast
enhancement can distinguish areas of active inflammation from older brain plaques.
MS lesions may also be visible on contrast-enhanced CT scans; sensitivity may be
increased by giving twice the iodine dose and delaying scanning (double-dose
delayed CT scan).
CSF is abnormal in the majority of patients. IgG may be > 13%, and lymphocytes
and protein content may be increased, but these findings are not pathognomonic.
Oligoclonal bands, which indicate IgG synthesis within the blood-brain barrier, may
be detected by agarose electrophoresis of CSF in up to 90% of patients with MS, but
absence of these bands does not rule out MS.
IgG levels correlate with disease severity.
Myelin basic protein may be elevated during active demyelination.
Evoked potentials are recorded electrical responses to stimulation of a sensory
system. Pattern-shift visual, brain stem auditory, and somatosensory evoked
potentials may be abnormally delayed early in the disease, because demyelination
slows the conduction of electrical impulses in these sensory pathways.
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Treatment
Pharmacological
Spontaneous remissions and fluctuating symptoms make treatments difficult to
evaluate.
Corticosteroids (oral prednisolone 60mg to 100 mg/day tapered over 2 to 3 weeks or
intravenous methylprednisolone 500mg to 1000 mg/day for 3 to 5 days) are the main
form of therapy. They may shorten the symptomatic period during attacks, although
they may not affect eventual long-term disability.
In patients presenting with acute severe optic neuritis the onset of MS may be
delayed by using high-dose intravenous corticosteroids.
Long-term corticosteroid treatment is rarely justified and can cause numerous
medical complications including osteoporosis, ulcers, and diabetes.
Alternatively, ACTH 40 u to 80 u/day intramuscularly for 5 days tapered over 2 to 3
weeks can be used but has been largely replaced by corticosteroid use.
Immunomodulatory therapy with Interferon- reduces the frequency of relapses in
relapsing remitting MS and may help delay eventual disability.
Glatiramer acetate may have similar benefits for early, mild MS.
Intravenous Gamma Globulins given monthly may help control relapsing MS
refractory to conventional therapies.
Immunosuppressive
drugs
(Methotrexate,
Azathioprine,
Cyclophosphamide,
Cladribine) for more severe progressive forms are not uniformly beneficial and have
significant toxic risks.
Drugs for spasticity such as Baclofen and Tizanidine can be initiated at a low
dosage and gradually increased until the patient responds.
Non Pharmacological
In debilitated patients prevention of bed sores and urinary tract infections is
essential. The need for self catheterisation has to be carefully evaluated.
Studies have shown that the prevalence of depressive symptoms in a population
based sample of people with M.S. is high. Given the serious nature of depression
and its association with worse self reported functioning and weak sense of
coherence, attention to, and treatment of mental health problems and depression
are strongly indicated in the clinical management of Multiple Sclerosis. [3]
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Multidisciplinary Rehabilitation.
Rehabilitation in MS is often driven by need rather than by the underlying severity of
the disease. Persons with MS are often young and diagnosed usually in the third
decade of their life. They have greater potential for neurospasticity and a longer
survival time over which to maximise functional and financial independence than the
brain injured population in general. Despite better education and advances in
disease modifying drugs, persons with MS are unemployed at a rate of 70%-80%
five years after diagnosis. This has adverse consequences for the individual and
society.
MS has a fluctuating nature (unlike stroke or spinal cord injury) and is a dynamic
process (as in relapsing/remitting form of MS). Rehabilitation is therefore an ongoing
effort not limited to a finite time, and requires more frequent visits to health
professionals compared with other neurological conditions. These persons may
require different programs of rehabilitation at different stages of their illness.
As MS is progressive, rehabilitation professionals should anticipate future needs,
services and equipment rather than when the situation reaches crisis point. In
accordance with guidelines, multidisciplinary rehabilitation services and programs
have been developed to serve the needs of the younger 'working age' adults with
MS. These are individualized programs and encompass all aspects of care including
personal, social and physical.
As the impact of MS extends to many aspects of a person’s life, an individualized,
multidisciplinary approach is essential and often in-patient rehabilitation is the most
appropriate setting to treat complex needs of these patients. Intensive in-patient
rehabilitation has been advocated to improve patient function (mobility, transfer
skills, gait).
Community and home based programs have broad outcomes that aim to reduce
impairment and disability, facilitate social reintegration and return to work with
financial independence, improved participation and psychosocial adjustments.
Persons with MS can present to rehabilitation services with various combinations of
deficits, such as physical, cognitive, psychosocial, behavioural and environmental
problems.
These include impairments (strength, coordination, balance, spasticity, memory,
urinary urgency), which result in disability or functional limitation (mobility, self care,
incontinence, pain, cognitive deficits) and limitation in performing their role in society
(participation), in accordance with the international classification of functioning,
disability and health (ICF) endorsed by the World Health Organization in 2001.
Therefore issues of progressive physical disability, psychosocial adjustment, social
reintegration, financial strain and impact on driving, work and family occur over time.
Systematic reviews show that multidisciplinary rehabilitation is effective in stroke
and traumatic brain injury populations, but the evidence base for the effectiveness of
multidisciplinary rehabilitation in patients with multiple sclerosis (MS) is not yet
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established. [4] [5]
A recent meta-analysis on the effectiveness of physical, functional and psychological
interventions in MS suggests that occupational therapy (OT) was beneficial in
treating deficits from MS. These findings may be biased as the final analysis
included pre-experimental design with no control group.
Further, another systematic review could make no recommendations on the efficacy
of individual OT interventions on functional ability, social participation and quality of
life in MS, due to lack of randomized controlled trials.
More recently a systematic review reported the effectiveness of exercise therapy
(alone), in terms of activities of daily living (ADLs) and positive outcomes related to
mood, anxiety and depression in MS. There was however no evidence that specific
exercise therapy programmes were more successful in improving ADLs than any
other exercise treatments. [4][6][7]
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Prognosis
The most commonly used scale to measure degrees of disability in patients with MS
is the Expanded Disability Status Scale of Kurtze (EDSS) [ Appendix 1]. This scale
ranges from 0, equivalent to no disability, and rises in increments of 0.5 to 10,
indicative of death from MS.
Studies indicate that the rate of progress through these disability milestones is time
related.
It was shown that median ages at time of assignment of irreversible disability were
44.3 years for a score of EDDS 4, 54.7 years for EDDS 6 and 63.1 years for EDDS
7. [8]
These results were essentially similar whether the initial course of Multiple Sclerosis
was exacerbating-remitting or progressive, and whatever the initial symptomatology.
Females reached disability milestones at an older age than males.
The most influential clinical factor was age at clinical onset of multiple sclerosis: the
younger the onset, the younger the age at assignment of disability milestones and
vice versa. Therefore, prognosis in Multiple Sclerosis appears, at least to some
extent, as duration dependent and not substantially affected by the initial course, be
it exacerbating-remitting or progressive.
Aside of acute focal recurrent inflammation and diffuse chronic neurodegeneration,
accelerated ageing-related mechanisms may operate in the central nervous system
of multiple sclerosis patients [9]
There is convincing evidence that neurological relapses in Multiple Sclerosis (MS)
are the clinical counterpart of acute focal inflammation of the central nervous system
(CNS)
whereas
neurological
progression
is
that
of
chronic
diffuse
neurodegeneration.
The classical view is to consider that MS is an organ-specific autoimmune disease,
i.e. that inflammation is the cause of the neurodegeneration. The succession of
relapses eventually leads to accumulation of disability and clinical progression
results from subclinical relapses. A series of recent observations tends to challenge
this classical concept.
Important observations have come from the study of the natural history of MS. In the
Lyon MS cohort, [10] accumulation of irreversible disability appeared not to be
affected by clinically detectable neurological relapses. This has also been shown to
be "amnesic" for the early clinical characteristics of the disease, and essentially age-
dependent.
Suppressing relapses by disease-modifying agents does not dramatically influence
the progression of irreversible disability. Beta Interferon reduces the relapse rate by
30% and conventional MRI activity by more than 50%. In spite of this effect on
inflammation, the effect on disability is only marginal and possibly relapse-reduction-
dependent.
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Administration of Campath-1h (Alemtuzumab) to patients with very active disease in
terms of frequency of relapses, accumulation of disability and MRI activity, results in
a profound, prolonged lymphopenia and the suppression of clinical and MRI activity,
but in spite of this, clinical disability and cerebral atrophy still progress.
The same experience has been reported with Cladribine and Autologous
Haematopoietic Stem Cell Transplantation.
All these observations give support to the fact that relapses do not essentially
influence irreversible disability in the long term in MS. They are consistent with what
has been shown at the individual level in the 1970s by performing serial quantitative
neurological examinations over several years, and with what is currently emerging
from early and serial structural brain MRI studies. These breakthroughs have
immediate implications for the counselling of patients with MS. They suggest that
MS is as much neurodegenerative as inflammatory, and should cause the
modification of disease-modifying therapeutic strategies by focussing on the
protection and repair of the nervous system and not only on the control of
inflammation. [9][10]
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Main Disabling Effects
The principle manifestations of MS are weakness of one or more limbs, spasticity,
muscle fatigue, unsteadiness of gait and difficulties with speech.
Tremor sufficient to interfere with upper limb function may occur and loss of
sensation may develop.
Difficulty in bladder control is common and may range from urge incontinence to full
incontinence requiring catheterisation.
As the disease progresses mobility problems become apparent and sufferers may
require the use of a walking aid. Difficulties may be due to weakness and spasticity
or because of unsteadiness leading to falls. When walking the severity of muscle
weakness may cause the person to have frequent falls.
Visual problems may also increase mobility problems and weakness or tremor of the
upper limbs may cause difficulty using walking aids.
With further progression these manifestations will give rise to difficulty with self care.
In addition the presence of depression or other mental health problem may cause
additional difficulty for patients with MS coping with Activities of Daily Living.
Some of the specific cognitive deficits observed in people with MS are:
Memory Dysfunction. This is the most commonly reported cognitive
dysfunction in MS and occurs in 20 to 44% of people with MS. The type
of memory deficit most often reported is free recall of recently learned
material. Free recall is the ability to get to a memory instantly - MS
rarely seems to affect a person's ability to get items into the memory
banks however it often takes much longer to retrieve.
Verbal fluency is affected in some people with MS whereas verbal
comprehension appears undamaged. Verbal fluency deficits usually
take the form of slowed free recall of words that describe concepts and
less often words that name objects.
Cognitive Fatigue. Continued attempts to remember names or finish
sentences can lead to continual slowing of a successful outcome.
Impaired planning skills. One study reported that 40% of people with ms
are less able to plan things than healthy controls. This study was
criticised because it was a timed test and may be influenced by recall
slowness than outcome difficulty.
In relapsing remitting MS spontaneous remission is common in the early stages of
the disease and indeed may be life long.
It is now considered that if symptoms resulting from relapse do not result in
remission within 6 months they are likely to be permanent.
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If the patient with MS becomes chair or bed bound then they will also require help to
move frequently to prevent the development of bed sores. [11]
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Appendix A - Expanded Disability Status Scale
(EDSS) of Kurtzle for Patients with Multiple Sclerosis
Overview :
Kurtzke modified the Disability Status Scale (DSS) to allow for finer gradings of disability. It
incorporates the functional system grades to help quantify the findings. The author is from
Georgetown University in Washington, D.C.
Functional Systems:
(1) pyramidal functions (P)
(2) cerebellar functions (Cll)
(3) brain stem functions (BS)
(4) sensory functions (S)
(5) bowel and bladder functions (BB)
(6) visual or optic functions (V)
(7) cerebral or mental functions (Cb)
(8) other functions (O)
Functional Level
Functional System Score
EDSS
normal neurologic examination
cerebral grade 0 to 1, others 0
0
no disability
minimal signs in 1 system other
1.0
than cerebral (one non-cerebral
FS =1)
no disability
minimal signs in > 1 system
1.5
other than cerebral (> 1 non-
cerebral FS =1)
minimal disability in 1 system
1 FS grade 2, others 0 or 1
2.0
minimal disability in 2 systems
2 FS grade 2, others 0 or 1
2.5
moderate disability in 1 system, fully
1 FS grade 3, others 0 or 1; or
3.0
ambulatory
3-4 FS grade 2, others 0 or 1
moderate disability in 1 system, fully
1 FS grade 3 and 1-2 FS grade
3.5
ambulatory
2, or 2 FS grade 3, or 5 FS
grade 2; others 0 or 1
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fully ambulatory without aids; self-
1 FS grade 4 alone, others 0 or
4.0
sufficient; up and about 12 hours a day;
1; combination of lesser grades
able to walk without aid or rest 500
exceeding pattern 3.0
meters
fully ambulatory without aids; self-
1 FS grade 4 alone, others 0 or
4.5
sufficient; up and about most of the day;
1; combination of lesser grades
able to work full day but may have some
exceeding pattern 3.0
limitations in full activity; may require
minimal assistance; able to walk without
aid or rest 300 meters
fully ambulatory without aids; unable to
1 FS grade 5 alone, others 0 or
5.0
work full day without special provisions;
1; combination of lesser grades
able to walk without aid or rest 200
exceeding pattern in step 4.0
meters
fully ambulatory without aids; self-
1 FS grade 5 alone, others 0 or
5.5
sufficient; unable to do full daily activities;
1; combination of lesser grades
able to walk without aid or rest 100
exceeding pattern in step 4.0
meters
intermittent or constant unilateral aid
>= 3 FS >=3
6.0
(cane, crutch, brace); can walk about 100
meters with or without resting
constant bilateral walking aids (canes,
>= 3 FS >=3
6.5
crutches, braces); can walk about 20
meters without resting
unable to walk more than 5 meters even
rarely pyramidal grade 5 alone;
7.0
with walking aid; essentially restricted to a more than 1 FS >= 4
wheelchair; can wheel self and perform
transfers alone; can use standard
wheelchair; up and about approximately
12 hours a day
unable to take more than a few steps;
more than 1 FS >= 4
7.5
restricted to a wheelchair; may need aid
in transfer; cannot carry on in standard
wheelchair 12 hours; may require
motorized wheelchair
restricted to bed or chair; may be out of
several systems >= 4
8.0
bed much of the day; retains many self-
care functions; generally has effective use
of arms
essentially restricted to bed much of the
several systems >= 4
8.5
day; has some effective use of the arms;
some self-care functions
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helpless in bed; can communicate and
most grades >= 4
9.0
eat
totally helpless in bed; unable to
almost all grades >= 4
9.5
communicate effectively; unable to eat or
swallow
death due to MS
10.0
References:
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status
index (EDSS). Neurology. 1983; 33: 1444-1452 (Appendix B, page 1451-1452).
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References
[1] Clinical Evidence: Neurological Disorders: Multiple Sclerosis Web publication 01 october
2005
[2] The Merck Manual of Diagnosis and Therapy. Sec. 14, ch:180.
[3] Gottberg K, Einarsson U, Fredrikson S, von Koch L and Widén Holmqvist L. A
population-based study of depressive symptoms in Multiple Sclerosis in Stockholm County.
Association with functioning and sense of coherence. J. Neurol. Neurosurg. Psychiatry
published online 17 Jul 2006; doi:10.1136
[4] Khan F, Turner-Stokes L, Ng L, Abrahamason S, Kilpatrick T. Multidisciplinary
rehabilitation for adults with Multiple Sclerosis. (Protocol) Cochrane Database of Systematic
Reviews 2006, issue 2.
[5] Management of Multiple Sclerosis in primary and secondary care National Institute for
Clinical Excellence. Clinical guideline 8, Nov. 2003
[6] Steultjens EMJ, Dekker J, Bouter LM, Cardol M, van de Nes JCM, van den Ende CHM.
Occupational therapy for Multiple Sclerosis (Cochrane Review). The Cochrane Database of
Systematic Reviews 2003, issue 3. art. No.: CD003608.
[7] Rietberg MB, Brooks D, Uitdehaag BMJ, Kwakkel G. Exercise therapy for Multiple
Sclerosis. Cochrane Database of Systematic Reviews 2004, issue 3. Art no.: CD003980
[8] Confavreux C, Vukusic S. Age at disability milestones in Multiple Sclerosis. Brain. 2006
Mar; 129 (pt. 3) : 561 – 563
[9] Confavreux C, Wertheimer P, Vukusic S. Accumulation of irreversible disability in
Multiple Sclerosis – lessons from natural history studies and therapeutic trials. J R Coll.
Physicians Edinb. 2004; 34:268 – 273
[10] Confavreux C, Vukusic S, Moreau T and Adeleine P. Relapses and progression of
disability in Multiple Sclerosis. N Engl J Med. 2000 Nov 16;343(20):1430-8.
[11] Aylward M, Dewis P, Scott T (Eds). The Disability Handbook – a Handbook on the Care
Needs and Mobility Requirements likely to arise from various Disabilities and Chronic
Illnesses. HMSO 1992
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