295 24

Multiple sclerosis and related

disorders
Abstract
Multiple sclerosis is a disease of the central nervous system that is the most common
cause of disability among young adults in the Western world. It is characterized by a
wide variety of neurological symptoms, a combination of new transient symptoms and
gradually progressive loss of function over a lengthy period. There are several types of
progression. The criterion for diagnosing it is abnormalities that are dissociated in time
and place. MRI is the most important diagnostic test. There is no causal treatment for
MS as yet, although there are immunomodulatory and immunosuppressive treatments.
There are also symptomatic treatments. MS needs to be distinguished from other demy-
elinating disorders.

24.1 Pathophysiology – 297

24.2 Clinical symptoms – 297

24.3 Progression – 298

24.4 Genetic and exogenous factors – 299

24.5 Diagnosing MS – 299

24.6 Treatment – 300

24.6.1 Lifestyle recommendations – 300
24.6.2 Shortening an exacerbation – 300
24.6.3 Influencing the course of the disease – 300
24.6.4 Treating the symptoms – 301
24.6.5 Supporting the patient and family – 302

24.7 Other diseases involving CNS demyelination – 302

24.7.1 Acute disseminated encephalomyelitis – 302
24.7.2 Transverse myelitis – 302
24.7.3 Neuromyelitis optica – 302

 lectronic supplementary material

E
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material, which is available to authorized users.

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J. B. M. Kuks and J. W. Snoek (Eds.), Textbook of Clinical Neurology, https://doi.org/10.1007/978-90-368-2142-1_24
24.8 Disorders resembling multiple sclerosis – 303
24.8.1 Neurosarcoidosis – 303
24.8.2 Neurological complications of systemic lupus erythematosus – 303
24.8.3 Neurological abnormalities in Sjögren’s syndrome – 303
24.2 · Clinical symptoms
Case 24.1
An 35-year-old woman has had gradually worsening gait
disorders for the past two years: she is no longer able to run
and her balance is impaired. In recent months she has felt as
if there is a tight band around her lower legs. She is unable
to handle small objects properly without looking at them. A
few years ago, shortly after a pregnancy, she had frequent
tingling in the fingers of her right hand at night. That has
gone now, but since then she has had twinges of tingling
running from the neck into both arms and via the spine to
the lower back when bending her neck.
For over a year she has been tired and she suffers from
shortness of breath in smoky rooms and after exercise.
When asked, she says she had a tick bite ten years ago.
Examination reveals the following abnormalities:
5 symmetrical very lively reflexes in arms and legs;
indifferent plantar reflexes
5 impaired sense of vibration in the ankles and impaired
stereognosis in the hands
5 first-degree nystagmus in all directions.
An MRI of the cervical spinal cord shows a central dense
abnormality on the T2 images. The brain MRI does not show
any abnormalities.
As a diagnosis of MS was considered, a lumbar puncture was
carried out. The composition of the CSF was slightly altered
due to increased protein (1.5 g/L), but the IgG index was
normal.
Question 1: What requirements must a diagnosis of MS meet?
Can it be diagnosed in this patient?
Question 2: MS can cause tingling in the fingers, but so can
other disorders. Which ones should be considered in this
patient’s case?
Question 3: What is causing the symptom elicited by bending
the neck?
Question 4: Which abnormalities in this case are consistent
with polyneuropathy and which are not?
Question 5: Is neuroborreliosis a likely diagnosis in this case?
Question 6: What other diagnoses could explain this
presentation?
Online: 7Answers to case study questions 24.1
24.1 Pathophysiology
Multiple sclerosis (MS) is a disease of the central nervous sys-
tem. Myelin is lost at various places (demyelination) due to an
inflammatory process involving lymphocytes and macrophages
that blocks nerve conduction. Before and during a demyelina-
tion event the blood-brain barrier is locally compromised for
a few weeks (7sect. 11.1.3). This can be seen as staining in a
T1-weighted MRI scan with contrast. The break in the blood-
brain barrier enables lymphocytes and macrophages to pene­
trate the brain and spinal cord. The patient often recovers after
a few weeks (remyelination), but gliosis can eventually develop
(sclerotic plaque). As demyelinated and remyelinated areas
produce the same high signal intensity on a T2-weighted MRI
297 24
scan, there is little correlation between abnormalities on a T2-
weighted MRI scan and the degree of neurological deficit.
MS also causes loss of axons, but whether this is due to
repeated demyelination or some other cause is unclear. Areas
of axonal damage can be seen as black holes on a T1-weighted
MRI scan, and the number of black holes does correlate fairly
closely with the degree of neurological deficit.
The demyelination and axonal damage cause neurological
(negative) symptoms. Loss of the isolating function of myelin
makes nerves more sensitive to mechanical irritation and ena-
bles electrical activity to be conducted between nerve fibres:
this produces symptoms of irritation (positive symptoms)
such as paraesthesia, neuralgia (7sect. 4.2.3) and myokymia
(7sect. 4.2.1).
The exacerbations and remissions characteristic of MS are
due to successive demyelination and remyelination. The pro-
gressive phase that often develops later is due to loss of neurons
and axons.
24.2 Clinical symptoms
The demyelination foci that develop in MS can occur through-
out the CNS, so the symptoms can be very varied. Some symp-
toms are fairly characteristic of MS (.fig. 24.1), especially in
young adults.
Impaired visual acuity. In approximately a quarter
of patients MS starts with optic/retrobulbar neuritis
(7sect. 16.2.2). Typical is impaired vision in one eye that deve­
lops over a period of hours or days; that eye is also somewhat
painful, especially when making eye movements. Patients with
optic neuritis are found to have a delayed response when the
visual evoked potentials (7sect. 4.5) are examined, even once the
symptoms have cleared up. The prognosis of optic/retrobulbar
neuritis is good (7sect. 16.2).
Sensory symptoms. These are often the first symptoms of MS.
To begin with they are often transient and do not cause much of
a problem, with the result that patients do not always seek medi-
cal assistance. The symptoms vary enormously in extent, severity
and nature (deafness, tingling, cold, burning, itching, band-like
tightness, a sensation like walking on cotton wool). Typical is a
gradual spread over a period of hours or days. If the posterior
columns of the cervical spinal cord are damaged, paraesthesia
(7sect. 4.2.3) can occur in the arms, along the back and some-
times in the legs when bending the head forward (Lhermitte’s
sign). It is not always easy to make an objective assessment of the
sensory symptoms using the standard tests. The extent to which
sensation is affected can be very erratic. Epicritic sensation is
more severely affected than protopathic sensation, as proto-
pathic sensory impulses are conducted mainly by unmyelinated
fibres. MS hardly ever causes complete analgesia.
Motor symptoms. These are usually pyramidal tract symp-
toms in the legs: the patient cannot walk fast, tends to stumble
more and tires from walking sooner. The arms may become
involved later, but often to a lesser extent. On examination the
patient finds hopping difficult. An early symptom of a pyrami-
dal tract disorder due to MS is absence of abdominal skin reflex.
 298 Chapter 24 · Multiple sclerosis and related disorders
normal 35
ataxia spastic
impaired tingling in paresis in
vision in left arm legs
right eye
infection
25 30 years
. Figure 24.1  Multiple sclerosis
Brainstem symptoms. Diplopia is common. Highly specific
to MS is internuclear ophthalmoplegia (7sect. 6.2.3). MS can
cause sensory impairments of the face, trigeminal neuralgia
(7sect. 21.3.1), facial palsy (7sect. 16.2.7) and attacks of dizzi-
ness (7sect. 16.2.8). Progressive MS causes dysphagia, often as
part of pseudobulbar syndrome (7sect. 6.6). The patient may
also have uninhibited emotional outbursts.
Cerebellar symptoms. These develop particularly in the pro-
gressive phase, and consist of unsteady gait, ataxia of one or
both arms and dysarthria. Saccadic eye movements and conju-
gate nystagmus develop early in the course of the disease and
are quite often found as subclinical symptoms on examination.
Micturition problems. Uninhibited detrusor activity
(7sect. 7.6.1) makes it difficult for the patient to retain urine.
Uncoordinated activity on the part of the detrusor muscle and
sphincters, on the other hand, causes difficulty voiding. Many
patients have both types of micturition problem.
Sexual function disorders are common, but patients often
do not mention them unprompted, and they can sometimes be
treated.
Abnormal fluctuating fatigue is the main problem for many
MS patients, sometimes preceding the development of specific
symptoms. The precise cause is not known.
Mental and cognitive symptoms. Depression is common.
Half of patients develop cognitive symptoms (memory prob-
lems, mild dysphasia) that can affect their work.
Symptoms that are very rare in MS are extrapyramidal dis-
orders, cortical syndromes such as aphasia, apraxia, agnosia,
hearing loss, severe dementia, marked disorders of protopathic
sensation, muscle atrophy (other than due to inactivity) and
areflexia. If a patient has these symptoms, the possibility of a
diagnosis other than MS (possibly along with MS) should be
investigated.
Disability can be expressed in general terms on a scale of 0
to 10 (the Expanded Disability Status Scale, EDSS, or Kurtzke
scale), where 0 = no problems or symptoms, 3 = clear prob-
lems and symptoms but full mobility, 6 = need for a walking
aid, 7 = wheelchair-bound, 9 = bed-ridden and 10 = death
from MS.
24
24.3 Progression
The initial symptoms develop between the ages of 20 and 40 in
70 % of cases, rarely (approx. 5 %) below the age of 15 or after
the age of 50. Twice or three times as many women as men are
affected, and women are often affected earlier than men. The
onset is preceded by infections more frequently than would be
expected by chance, and there is some predilection for the ini-
tial symptoms to develop in the first three months after a preg-
nancy. There is usually no clear provocation, however.
Main symptoms of multiple sclerosis
early stage (%) late stage (%)
impaired visual acuity 25 50
brainstem 15 35
paresis, spasticity 40 90
sensory 40 90
cerebellar 20 80
micturition problems 5 60
cognitive 20 50
In 40 % of patients the symptoms develop within a few hours,
in 30 % within one or more days (up to a week); in the remain-
der within a period of weeks or months. In 80 % of patients the
initial symptoms clear up completely in the course of weeks or
months, although after this minor abnormalities can still be
found on neurological examination (nystagmus, reflex differ-
ences, pathological plantar reflex).
An MS attack or exacerbation is referred to as a ‘relapse’
or ‘Schub’ (the German term). In some patients a rapid rise
in body temperature (fever, hot bath) can bring new transient
symptoms to light or temporarily exacerbate existing symp-
toms. These clear up again when the temperature goes back to
normal.
Approximately 80 % of patients have a progression involv-
ing regular relapses and remissions (once or twice every two
years: relapsing-remitting MS or RRMS). During the course
of the MS the exacerbation frequency decreases, after which
gradually progressive neurological symptoms develop. This is
referred to as secondary progressive MS or SPMS. On average
SPMS begins 15 years after RRMS, but the individual spread is
enormous. A maximum of 10 % of patients are spared the pro-
gressive phase (benign MS). A very rare condition is malignant
MS, a fulminant type with brainstem and cerebral symptoms
that can cause death within days or weeks (Marburg’s variant).
Also rare is a type of MS that starts with a very large demyeli-
nation focus that displaces surrounding structures (tumefactive
MS). Following steroid treatment the prognosis for this is good.
In 15–20 % of patients the course is gradually progressive
from the start (primary progressive MS): these are fairly often
patients aged 35 to 50, equally distributed among men and
24.5 · Diagnosing MS
women (unlike in the case of RRMS). This condition usually
causes slowly progressive myelopathy. It is more difficult to
diagnose because of the absence of the characteristic relapses
and the older age on presentation.
Of all MS patients, an estimated 50–70 % are still able
to work after five years of the illness, 40–50 % after ten years,
25–30 % after 15 years and 20 % after 20 years.
The prognosis is relatively good if the illness begins with optic
neuritis or sensory symptoms and the MRI shows few lesions at
the time of diagnosis. The prognosis is poorer for patients who
start with pyramidal, cerebellar or brainstem symptoms or mic-
turition problems and have a high exacerbation frequency in the
first few years, incomplete recovery after the first exacerbations
and a large number of lesions on the initial MRI scan.
MS reduces life expectancy by five to ten years, usually as a
result of decubitus ulcers or sepsis.
24.4 Genetic and exogenous factors
First-degree relatives of MS patients are at higher risk of MS
than the general population, so this may point to genetic pre-
disposition. A stronger argument is that shared MS is far more
common in monozygotic twins (30 %) than dizygotic twins
(4 %). Genes related to immune response are particularly
involved: HLA-DR2 is found in 70 % of MS patients, as against
25 % of the general population.
Epstein-Barr virus (EBV) is one of the suspected exogenous
factors. Of all MS patients, 99–100 % have antibodies to EBV,
as against 85–95 % of the adult population. How EBV infec-
tion causes an increased risk of MS is not known. It may be that
current or past parasitic infections actually play a protective
role.
MS is more common in moderate climate zones than in
the tropics. The prevalence decreases with latitude: 60–80 per
100,000 in the Scandinavian countries, 50–75 per 100,000
in Britain, Germany and the Netherlands, 20 per 100,000 in
Southern France and Italy, and 5 per 100,000 among the indi­
genous populations of South Africa and the Netherlands Antil-
les. It has also been found that people aged 15 or over who
move from a moderate to a tropical or subtropical climate
retain the risk of MS in their country of birth, whereas children
well below the age of 15 at the time of immigration have the
same MS frequency as the indigenous population of their new
countries. This suggests a role for climate, sunlight or infection
level. It may be that this association is mediated partly by vita-
min D, which is produced in the skin by the action of sunlight
and has immunomodulatory effects.
Lastly, it should be noted that smokers are at higher risk of
MS.
24.5 Diagnosing MS
Many symptoms and signs of MS can be caused by other dis-
eases, some of which (fatigue, transient tingling) can even
occur in healthy individuals. Characteristic of MS, then, is not
299 24
the nature of the symptoms but their chronological course: the
occurrence of problems and symptoms in episodes, which must
by definition last more than 24 hours, but usually persist for
days or weeks (sometimes months).
MS should therefore be considered if a young adult has sev-
eral episodes of neurological symptoms over time, each attrib-
utable to a different part of the CNS (referred to as dissociation
in time and place).
The principle that symptoms consistent with MS must be
dissociated in time and place is the basis of the internationally
accepted McDonald diagnostic criteria.
There is dissociation in place if neurological examination
finds abnormalities that can only be attributed to more than
one lesion in the CNS, or if an MRI scan shows lesions in vari-
ous areas of the CNS.
There is dissociation in time if a patient develops new objec-
tive symptoms, or new lesions are found on a repeat MRI scan.
Not every white spot on an MRI scan counts: specific to MS,
and included in the McDonald criteria, are lesions around the
ventricles (periventricular), directly adjacent to the cortex (jux-
tacortical), in the brainstem and cerebellum (infratentorial)
and in the spinal cord (.fig. 24.2). The diagnostic criteria also
include ruling out other possible explanations for the symptoms.
Nowadays a diagnosis of MS is often considered once an
MRI scan after a first exacerbation shows abnormalities typi-
cal of MS. As there is no dissociation in time yet, this does not
meet the MS criteria, and it is referred to as a clinically isolated
syndrome (CIS).
A positive CSF test is only included in the criteria for a
diagnosis of PPMS. An elevated IgG index or oligoclonal bands
(7sects. 10.5 and 10.6) supports a diagnosis of MS. A CSF test
can also be useful for other types of MS in doubtful cases. Pleo-
cytosis of more than fifty cells per cubic millimetre or an exces-
sively high protein level argue against a diagnosis of MS.
Differential diagnosis of multiple sclerosis
5 vasculitis, e.g. Wegener’s disease, SLE (7sect. 24.8.2) or
Susac syndrome
5 other vascular diseases, e.g. Fabry disease and CADASIL
(7sect. 17.4.7)
5 neuroborreliosis (7sect. 23.9)
5 paraneoplastic syndromes (7sect. 22.7)
5 HIV (7sect. 23.5) and HLTV-1 infection (7sect. 15.6.5)
5 neurosyphilis (7sect. 23.8)
5 progressive multifocal leukoencephalopathy
(7sect. 23.5.3)
5 granulomatous disorders (7sect. 24.8.1)
5 leukodystrophy (7sect. 28.4.2)
5 adult X-linked adrenoleukodystrophy (7sect. 28.4.2)
5 vitamin B12 deficiency (7sect. 15.6.3)
5 Chiari malformation (7sect. 15.5.5)
5 extradural spinal cord compression (7sect. 15.5)
5 processes in the optic chiasm or behind the orbit
5 tumours of the brainstem and cerebellum
5 a functional disorder
 300 Chapter 24 · Multiple sclerosis and related disorders
. Figure 24.2  MRI scans of a 34-year-old man with multiple sclerosis.
There are hyperdense abnormalities, periventricular and just below the
cortex (juxtacortical). a Transverse T2-weighted image; b sagittal FLAIR
image showing the same abnormalities and a small infratentorial
abnormality (in the cerebellum)
24.6 Treatment
24.6.1 Lifestyle recommendations
There is limited scope for influencing the course of the dis-
ease with lifestyle recommendations. The most important one
is probably to stop smoking. There are strong indications that
smoking not only increases the risk of MS but also adversely
affects its progression.
24
Psychological stress and infections are also likely to be bad
for MS patients. Avoiding stress and infections is easier said
than done, however.
There is no evidence that diets or dietary supplements are
useful. A good deal of research is currently taking place into
the role played by relative vitamin D deficiency, which is found
in many MS patients. There is as yet no evidence that taking a
vitamin D supplement has a beneficial effect on the progression
of MS.
24.6.2 Shortening an exacerbation
Corticosteroids speed up recovery from acute exacerbations
but do not affect their outcome or the long-term course of the
disease. If an exacerbation is incapacitating, a three or five-day
course of high-dose methylprednisolone (a total of 2,500–3,000
mg) can be administered intravenously. There are indications
that an oral booster course is more or less equally effective.
24.6.3 Influencing the course of the disease
All the drug treatments used to influence the long-term course
of the disease work by changing the mechanism of the immune
system or suppressing it. The main aim of these treatments is to
reduce the number of exacerbations and avoid, or at least delay,
permanent loss of function and disability.
The ‘first-line treatments’ are drugs with proven but limi­
ted effects. They do not usually have severe adverse effects.
They include dimethyl fumarate (DMF), glatiramer acetate
(GA), interferon beta (IFN beta) and teriflunomide. Second-
line treatments are more powerful but also have more severe
adverse effects and are only used once first-line treatments have
failed. These include alemtuzumab, fingolimod, mitoxantrone
and natalizumab.
All the available drugs have a proven effect on RRMS and
usually also on clinically isolated syndrome. The effect on
SPMS is at most marginal, and none of the drugs are effective
against PPMS.
These are generally very expensive treatments (costing over
10,000 euros per year).
First-line treatments
It takes longer on average for patients with a clinically isolated
syndrome treated with a first-line drug to have a second exac-
erbation, and there are indications that the risk of permanent
disability is lower. Treatment generally needs to be started
quickly for patients with a unfavourable prognosis based on the
clinical presentation and MRI findings. For others, immediate
treatment can be dispensed with provided they are monitored
regularly, ideally using MRI, as MS has a benign course without
treatment in some patients. Unfortunately it is difficult to pre-
dict which patients these will be: there are predictors at group
level, but they are unreliable in individual cases.
24.6 · Treatment
In the case of RRMS patients it is a good idea to weigh up
the expected beneficial and adverse effects of medication with
them. If there are indications of disease activity (exacerba-
tions and/or an increase in abnormalities on the MRI scan) it
is advisable to start treatment. The first-line drugs reduce the
number of exacerbations by between approximately 30 % (GA,
IFN beta and teriflunomide) and 50 % (DMF). The number of
abnormalities on the MRI scan (T2 lesions and cerebral atro-
phy) increases less rapidly and there are indications that per-
manent disability develops less quickly. These effects have been
shown for the first few years of treatment, but as no placebo-
controlled trials with a follow-up of three years or more have
been done we cannot be absolutely certain that these treat-
ments eventually produce a worthwhile decrease in disability
for patients.
DMF has to be taken orally twice a day. The main adverse
effects are gastrointestinal disorders and ‘flushing’, especially
during the first few months. Patients can eventually develop
lymphopenia.
GA has to be administered subcutaneously, and this often
causes skin irritation. It does not produce any flu-like effects.
There are indications that GA is somewhat more slow-acting
than IFN beta.
IFN beta has to be injected subcutaneously or intramuscu-
larly and, especially during the first three months, causes flu-
like symptoms and sometimes a temporary exacerbation of
the MS symptoms, in particular spasticity. It often causes skin
irritation around the injection sites. During the course of treat-
ment patients can develop neutralizing antibodies to IFN beta,
which negate its effect.
Teriflunomide has to be taken once a day. It is not a good
choice for female MS patients who want (or might want) to
have a baby, because of its teratogenic properties combined
with very slow elimination from the body once discontinued
(over one year).
Which of these drugs is best needs to be decided in each
individual case, and the best results are achieved with shared
decision-making between the patient and the doctor.
Second-line treatments
If a first-line drug proves ineffective, treatment with a second-
line drug needs to be considered.
There is a good deal of experience of using natalizumab.
This monoclonal antibody prevents immunocompetent cells
invading the CNS by binding to adhesion molecules. The treat-
ment is an intravenous drip that has to be administered every
four weeks. Over a two-year treatment period the risk of new
exacerbations is reduced by almost 60 % The risk of perma-
nent disability also goes down, and the number of new lesions
on the MRI scan is sharply reduced. Most patients experi-
ence hardly any adverse effects. In practice we regularly find
that patients who used to have active MS in spite of treatment
become completely stable with natalizumab. A rare adverse
effect is progressive multifocal leukoencephalopathy (PML:
7sect. 23.5.3). This is an infection of oligodendrocytes with JC
virus, which is indolent in half of the healthy population but
can become active in people with a compromised immune
301 24
system. The risk of PML is 1–4% in serological carriers of JC
virus, otherwise virtually zero. The treatment must be discon-
tinued immediately if a patient develops PML. Even if this is
done, PML usually causes severe permanent loss of function,
and death in 20 % of cases. Natalizumab treatment is therefore
not generally given to JC virus carriers, and existing treatment
needs to be reconsidered if a patient becomes seropositive dur-
ing treatment.
Another second-line drug is fingolimod, which is taken
orally once a day. Fingolimod prevents lymphocytes involved
in MS from leaving peripheral lymph nodes. This reduces the
risk of new exacerbations by 54 % over a two-year period. The
risk of permanent disability also goes down, and the number
of new lesions on the MRI scan is sharply reduced. Specific but
uncommon adverse effects are bradycardia at the start of treat-
ment, a slight rise in blood pressure, impaired liver function,
varicella zoster infection and macular oedema. The risk of PML
is far lower than with natalizumab.
There has been less experience as yet, relatively speaking,
of using alemtuzumab. This is a monoclonal antibody that
selectively disables B and T cells. The treatment consists of
short courses of daily intravenous drips at one-year intervals.
Compared with IFN beta, alemtuzumab reduces the number
of exacerbations by approximately 50 %, there are fewer new
lesions on the MRI scan and the rate at which permanent dis-
ability develops is slower. The main adverse effect is the deve­
lopment of autoimmune disorders: after five years’ treatment
40 % of patients develop autoimmune thyroiditis. Far less com-
mon are autoimmune thrombocytopenia (AITP) and Good-
pasture syndrome. No cases of PML due to alemtuzumab have
been reported, albeit the risk of infectious diseases is slightly
increased.
The cytostatic drug mitoxantrone has a beneficial effect
on exacerbation frequency (a 66 % reduction), degree of dis-
ability and number of lesions on the MRI scan. The number of
treatments is limited by its cardiotoxicity, however. It has the
familiar adverse effects of cytostatics, although mitoxantrone is
usually well tolerated at the standard dosage. In the long term
there is a risk of acute myeloid leukaemia. Its use has declined
in recent years because of these adverse effects and the advent
of other second-line drugs.
24.6.4 Treating the symptoms
If there is spasticity it is important to deal with precipita­
ting factors (urinary tract infection, unsuitable wheelchair).
Drugs (baclofen, tizanidine or dantrolene) can also help. As
these drugs reduce the tone of all the muscles, the price that
patients pay for using them can be impaired walking function.
For patients with severe spasticity, treatment with intrathecal
baclofen (a baclofen pump) can be considered. This is effective,
but it causes flaccid weakness of the legs, so it is only an option
for patients who have lost all standing balance and walking
function. If the spasticity is confined to a few muscle groups,
local treatment with botulinum toxin can help.
 302 Chapter 24 · Multiple sclerosis and related disorders
The potassium channel blocker 4-aminopyridine improves
conduction in demyelinated axons. It can have effects on a
variety of functions. So far it has been established that it can
improve walking speed slightly in some MS patients. To what
extent this constitutes a major improvement in the day-to-day
lives of MS patients is still a matter of debate.
Micturition problems can often be improved with drugs.
In many cases urological tests can be helpful in selecting the
right treatment strategy. Severe urge problems can be treated by
injecting botulinum toxin into the detrusor muscle. A propor-
tion of patients who develop significant urinary retention need
to carry out intermittent self-catheterization because of the
danger of vesicoureteral reflux. Regular urological check-ups
and proper treatment of urinary tract infections are needed.
Sexual function in men can be improved using a PDE5
inhibitor (e.g. sildenafil).
Fatigue is treated with amantadine. Some patients benefit
from occupational therapy (energy management).
The treatment of neuropathic symptoms (7sect. 4.2.3) has
already been discussed (7sect. 14.2.4).
24.6.5 Supporting the patient and family
It goes without saying that patients need to be given a lot of
information during the phase immediately after diagnosis.
Given the chronic nature of MS, however, specialist support
will still be needed subsequently, and the intensity of this will
depend on the course of the disease and any treatment given.
More and more hospitals have specialist nurses who are
able to take over supporting MS patients from the neurologist.
Generally speaking, the treatment is multidisciplinary, invol­
ving rehabilitation specialists, paramedics, medical psycholo-
gists, social workers and others.
There is a trend towards developing specialist MS centres
and using the internet and social media.
There are many ways of adapting homes and providing day-
to-day aids.
24.7  ther diseases involving CNS
O antibodies to myelin oligodendrocyte glycoprotein (MOG). In the
demyelination
24.7.1 Acute disseminated encephalomyelitis
Acute disseminated encephalomyelitis (ADEM) develops fol-
lowing a viral disorder or vaccination. The symptoms can be
impaired consciousness, fits, fever, unilateral or bilateral optic
neuritis (7sect. 16.2.2), meningism and focal neurological
abnormalities. In mild cases it is difficult to decide whether a
patient has had a first MS relapse. There are multifocal abnor-
malities on the MRI scan, which are stained when a contrast
agent is administered (unlike the abnormalities found in MS).
Lesions are also found in the thalamus and basal ganglia, again
unlike in MS. The CSF displays mild lymphocytic pleocytosis
24
and a slight increase in protein level. Indications of intrathe-
cal Ig synthesis (7sect. 10.5) are less common than in MS, par-
ticularly in the case of children with ADEM. The treatment is
intravenous corticosteroids. In severe cases this is followed
by intravenous immunoglobulin, cyclophosphamide and/or
plasmapheresis. The prognosis varies, with approximately 8 %
mortality but also 50 % complete remission. When considering
a diagnosis of ADEM it should be remembered that, except in
children, the disease is far less common than MS.
24.7.2 Transverse myelitis
Transverse myelitis starts with paraesthesia, back pain or weak-
ness in the leg muscles. There is usually no sharp dividing line
between the motor and sensory symptoms, which can ‘creep
up’ over a period of time. Unlike in MS, but as in neuromyeli-
tis optica, all the functions of the spinal cord (sensation, motor
function, bladder function) are affected simultaneously. Remis-
sion occurs in 40 % of patients; 20 % are left with severe per-
manent loss of function. The syndrome can occur in isolation,
but also in connection with SLE, Sjögren’s syndrome and after
a variety of infections, e.g. Mycoplasma pneumoniae, measles,
herpes zoster or herpes simplex virus and other viruses.
24.7.3 Neuromyelitis optica
Neuromyelitis optica (NMO) is an autoimmune disorder usu-
ally caused by antibodies to aquaporin-4, a water channel
found in astrocytes. The classic symptoms are optic neuritis
(7sect. 16.2.2) in one or both eyes and myelitis with severe para­
plegia of the legs. The two symptoms can occur either simulta-
neously or separately, in a course with relapses and remissions,
and patients recover less well than from MS. An MRI scan of
the spinal cord shows large lesions (involving more than three
spinal cord segments) but shows no abnormalities suggestive of
MS in the brain. Sometimes patients have only recurring optic
neuritis or only recurring myelitis. Antibodies to aquaporin-4
are found in 70–80 % of patients; in the remainder sometimes
acute stage the CSF usually contains leukocytes and elevated
protein, but oligoclonal bands (as found in MS) are usually
absent. The disease develops around the 30th year of life on
average (with a spread of five to 55 years), and it is relatively
common in people who also have other autoimmune disorders.
Acute exacerbations are treated with corticosteroids or plasma-
pheresis. Azathioprine or the monoclonal B cell antibody ritux-
imab is used to prevent new exacerbations.
It has now been found that some patients do have aqua-
porin-4 antibodies but only lesions outside the spinal cord and
optic nerves, e.g. in the hypothalamus or medulla oblongata
(hiccups being a strikingly common symptom). This is referred
to as NMO spectrum disorder.
24.8 · Disorders resembling multiple sclerosis
303 24
24.8 Disorders resembling multiple sclerosis 24.8.3 Neurological abnormalities in Sjögren’s
syndrome
In practice, most patients who are sent to a specialist MS clinic
for a second opinion and found not to have MS have a combi- If a patient with a syndrome consistent with MS also has dry
nation of less specific symptoms (fatigue, dizziness, tingling, a eyes or dry mouth, or arthritis symptoms, a diagnosis of sicca
feeling of weakness with no clear paresis) and MRI scans show- syndrome (Sjögren’s syndrome) should be considered. This dis-
ing abnormalities in the deep white matter of the brain (i.e. ease can also cause transverse myelitis, aseptic meningitis,
not in the classic periventricular, juxtacortical or infratentorial paroxysmal cranial nerve palsy, peripheral neuropathy and sen-
areas). ‘Non-specific’ MRI findings of this kind are common in sory neuronopathy (7sect. 13.7.2).
patients aged over 40, especially those who have hypertension
or are smokers. Abnormalities are never seen in the spinal cord,
unlike on MRI scans of MS patients.
The disorders discussed below are rare and usually easy to
distinguish from MS, but they can cause diagnostic problems.

24.8.1 Neurosarcoidosis

Sarcoidosis can affect many other organ systems besides the

lungs. Approximately 5 % of patients with sarcoidosis have neu-
rosarcoidosis, and in half of them this is the first manifestation
of sarcoidosis. There can be involvement of peripheral nerves
(up to acute polyradiculoneuritis, 7sect. 13.3.2), muscles, the
spinal cord, cranial nerves (especially CN VII and CN II), the
meninges with obstructive hydrocephalus, the pituitary gland/
hypothalamus and the cerebral hemispheres. It can be dif-
ficult to distinguish between neurosarcoidosis and MS from
an MRI scan. If MRI scans with contrast show lesions that
continue to enhance for more than a few weeks or enhancing
meninges, this suggests sarcoidosis. The CSF may show pleo-
cytosis, elevated albumin level, elevated IgG index and elevated
ACE and/or lysozyme level. This diagnosis should ideally be
based on examination of tissue from outside the nervous sys-
tem. The prognosis for cranial nerve palsy is good, even if left
untreated, unless the optic nerve is involved. Hydrocephalus
is an indication for a ventriculoperitoneal drain. Patients need
to be treated with high-dose corticosteroids for a few months,
often followed by maintenance treatment, with methotrexate if
appropriate. If there is no change in the symptoms, a different
diagnosis needs to be considered.

24.8.2 Neurological complications of systemic

lupus erythematosus

SLE can produce a wide variety of neurological and psychiatric

symptoms that are often easy to distinguish from MS. This is
more difficult in the case of transverse myelitis and optic neu-
ritis, which can also be caused by SLE. If the presenting symp-
toms of SLE are neurological it is difficult to make a diagnosis.
SLE is often only considered once additional symptoms (arthri-
tis, glomerulonephritis, Raynaud’s syndrome, haematological
abnormalities) develop. An MRI scan may show lesions in the
white matter, which tend to be subcortical rather than periven-
tricular. Serological tests can help, but elevated titres of antinu-
clear antibodies (ANA) are also found fairly often in MS.