Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2683_Библиотеки_им_академика_М_И_Перельмана.pdf
Nervous system
HINTS AND TIPS
Reflex anoxic seizures following a faint are
common, especially if the patient remains in an
upright posture.
Investigations
Bedside
The diagnosis is clinical, and a good eyewitness account
of the ‘seizures’ is vital. After a thorough history has been
taken and a thorough examination to consider differential
diagnoses, blood tests, including full blood count, measurement of urea and electrolytes, measurement of serum
calcium and magnesium, liver function tests and measurement of glucose, should be performed. An arterial blood
sample taken during or just after the seizure will often show
a metabolic acidosis, which will normalize rapidly after cessation of the seizure. It may be necessary to screen blood
and urine for drugs/toxins. A chest X-ray and ECG should
be performed.
Imaging
Neuroimaging such as CT or MRI helps identify structural
abnormalities that can cause seizures. MRI is the modality of
choice. It is especially important when epilepsy develops in
adulthood or in the very young (<2years), for focal seizures
and if first-line AEDs are not successful. Neuroimaging is
not recommended in clear diagnosis of genetic generalized
epilepsy.
Electroencephalogram
EEG is performed only to support the diagnosis, as 10%–15%
of the general population may have an ‘abnormal’ EEG and
approximately 15% of people with epilepsy never have specific epileptiform discharges. However, it may help further
identify the type of epilepsy. NICE recommends that if a standard EEG is not helpful, a sleep EEG should be performed.
Management
Drug treatment
Drug treatment should not be started unless a diagnosis
of epilepsy is confirmed. AEDs should be prescribed individually, with use of the lowest dose to obtain complete
seizure control with minimum side effects. A single drug
will suffice in approximately 80% of patients, the remainder
needing a second drug to achieve acceptable control. Partial
epilepsy is more likely to be refractory.
After a drug has been chosen, the dose is gradually
increased until control is achieved, the maximum dose is
reached, or toxic effects supervene. In the latter two cases,
alternatives need to be considered (see later).
Sodium valproate is the drug of choice in generalized
and unclassifiable epilepsies, and lamotrigine is the drug
of choice in focal epilepsies. Carbamazepine, phenytoin
and barbiturates all induce hepatic enzymes and therefore
speed up the metabolism of oestrogens and progestogens,
making the oral contraceptive pill unreliable. Sodium valproate does not affect oral contraceptive efficacy, but carries
a significant risk of teratogenicity. Buccally administered
midazolam or rectally administered diazepam for use in the
community is prescribed only for patients with a history of
prolonged or serial convulsive seizures. If treatment with a
new drug is commenced, it is introduced and the dose is
increased gradually while use of the old drug is withdrawn
sl owly.
Treatment is first instituted according to the specific epilepsy syndrome; if this is not clear, it is started according to
the seizure type.
First-line drugs
Focal onset seizures—Carbamazepine and lamotrigine
are the first-line therapies. Levetiracetam, oxcarbazepine
or sodium valproate can be offered if carbamazepine and
lamotrigine are contraindicated. Carbamazepine may cause
central nervous system (CNS) side effects (e.g. dizziness,
nausea, headaches and drowsiness), which may be avoided
by slow increase of the dose. It may increase or decrease serum phenytoin levels depending on the individual.
Generalized onset seizures—Sodium valproate is recommended as the first-line treatment. Lamotrigine can be
offered if sodium valproate is contraindicated but it may
exacerbate myoclonic seizures. Carbamazepine may be
considered but it may exacerbate myoclonic or absence seizures. Common unwanted effects of sodium valproate include weight gain, hair thinning and tremor.
Focal onset with impaired awareness (absence) seizures—Ethosuximide or sodium valproate is offered; if
these are contraindicated, lamotrigine can be used.
Myoclonic seizures—Sodium valproate is the first-line
treatment; if contraindicated, levetiracetam or topiramate
can be used.
Second-line drugs
Phenytoin is useful but less commonly used because of its
unpredictable pharmacokinetics. NICE suggests that the
newer AEDs (e.g. lamotrigine, levetiracetam, topiramate,
clobazam, gabapentin) be used as second-line agents if
valproate and carbamazepine are contraindicated or ineffective. Carbamazepine, gabapentin, oxcarbazepine,
phenytoin, pregabalin, tiagabine and vigabatrin are not recommended if absence or myoclonic seizures are present.
Withdrawing drugs
Most patients are seizure-free within a few years of starting therapy, and 60% remain so after drug withdrawal.
Therefore drug withdrawal is considered in some patients
after a period of therapy if they have been seizure-free
288
Intracranial tumours
3232
for 2years or more. Withdrawal should be achieved over
a period of at least 2–3months, one medication at a time.
Certain factors increase the risk of seizure recurrence, such
as abnormal EEG, abnormalities on neurological examination or certain types of epilepsy (e.g. juvenile myoclonic
epilepsy). The risk of withdrawal should be assessed on an
individual basis and carefully explained to your patient.
Other treatment
Surgery is sometimes needed for refractory, drug-resistant
epilepsy. It is most effective for focal onset seizures when
the focus of the abnormal electrical activity can be accurately localized and resected.
Behavioural and psychological interventions can be
tried. A ketonic diet (high fat, moderate protein, low carbohydrate) diet may be considered in children and young
adults when seizure control is difficult. Cognitive behavioural therapy or relaxation may be tried as adjuvant
therapy. Vagus nerve stimulation can be used in patients
who are refractory to AEDs and not suitable for surgery.
Status epilepticus
This is a medical emergency, and is defined as prolonged
generalized onset seizures lasting more than 5 minutes, or
repeated seizures without intervening recovery of awareness. The clear majority of seizures are tonic–clonic in
motor type. Both the risk of permanent brain damage and
mortality are related to the length of the attack, and therefore seizures must be stopped as soon as possible.
The ABCDE approach should be used initially:
• Secure the airway and administer high-flow oxygen.
Airway adjuncts may need to be used. The patient may
require intubation.
• Lay the patient in the recovery position if the cervical
spine has been cleared and the motor type will permit
it; remove false teeth.
• Check capillary glucose level.
• Gain IV access and take blood samples for arterial
blood gas measurements, full blood count,
measurement of urea and electrolytes, liver function
tests, measurement of calcium, magnesium and
clotting, and laboratory measurement of glucose.
Consider checking anticonvulsant levels if appropriate.
Consider doing a toxicology screen and blood/urine
cultures.
• Treat hypoglycaemia with 75–80 mL of intravenously
(IV) administered 20% glucose over 10–15 minutes.
• Administer lorazepam IV (0.1 mg/kg; usually a 4-mg
bolus is given); IV diazepam and buccally administered
midazolam are alternatives.
• If seizures persist, consider IV administration of
phenytoin or phenobarbital (with cardiac monitor).
• If seizures persist, consider general anaesthesia
with an infusion of one of the following: propofol,
midazolam or thiopental sodium (the latter is
the agent of choice in paediatric patients). EEG is
necessary for refractory status epilepticus.
After seizure, further investigations typically include chest
X-ray, ECG, neuroimaging and lumbar puncture.
Pregnancy and epilepsy
There are several important issues to be considered when an
epileptic patient wants to become, or becomes, pregnant (it
• The effect of AEDs on the fetus: several AEDs,
including carbamazepine and valproate, are teratogenic.
Are the drugs necessary?
• The effect of pregnancy on the mother's seizures and
the risk to the fetus from maternal seizures.
It is imperative to counsel the patient regarding these issues so that informed choices can be made. If it is felt that
antiepileptic therapy must continue during pregnancy, it is
important to try to use a single agent at the lowest possible
dose.
Driving and work and epilepsy
Current regulations stipulate that after a single unprovoked
seizure, the patient must not drive for 6months. If a diagnosis of epilepsy is made, the patient must be seizure-free for
at least 1year before driving can be recommenced. Longer
periods are necessary for drivers of large commercial vehicles. When a seizure at work would pose a significant risk
to the patient or the patient’s colleagues, this needs to be
carefully discussed.
Sudden unexpected death in epilepsy
Patients with epilepsy are at higher risk of sudden death,
termed ‘sudden unexpected death in epilepsy’ (SUDEP).
Certain features, which are mainly relate to the severity of
the epilepsy, place patients at higher risk, such as seizure
frequency and duration of disease. Patients should be informed and counselled regarding this issue.
INTRACRANIAL TUMOURS
General overview
These can be primary or secondary. Primary brain tumours
originate in the brain, whereas secondary brain tumours are
cancers that have spread to the brain from somewhere else in
the body (metastases). Primary brain, other CNS and intracranial tumours account for around 3% of all cancers. The
incidence of these is rising, and it is estimated it will reach
22 per 100,000 by 2035 from 13 per 100,000 in 2011. Most
benign neoplasms occur in the meninges, whereas most
malignant tumours are in the brain tissue. Because of their
location and threat to health, even if 'benign', they are often
289
Nervous system
classified as high-grade (rapidly growing and aggressive) or
low-grade (slow growing) tumours rather than benign or malignant. Certain familial conditions, such as neurofibromatosis, tuberous sclerosis and Li-Fraumeni syndrome predispose
to development of primary brain tumours. Secondary intracerebral tumours are the most common, and occur in up to
30% of cancers; mainly they are from lung, breast, kidney,
stomach, colon and rectum, skin, ovary, prostate or thyroid
cancers. The main types of primary brain cancers are shown
in Table32.2. More than 130 different types of brain, CNS
and intracranial tumours have been identified. Astrocytomas
are the most common, and account for almost 35% of cases.
Meningiomas are the second most common type (21%). The
overall 1-year survival rate for patients with primary intracerebral tumours is less than 50%. Complete recovery from
meningiomas may occur if they are removed completely.
Clinical features
Symptoms arise from the direct effects of the mass on surrounding structures, from raised ICP or by provocation of
seizures. Similar symptoms may be produced by any mass
lesion (e.g. haematomas, aneurysms, abscesses, tuberculomas, granulomas and cysts).
Direct effects depend on the site of the tumour:
• Frontal lobe: personality changes, social disinhibition,
emotional instability and impairment of intellectual
function. There may be anosmia, contralateral
hemiparesis or expressive aphasia (Broca area).
• Parietal lobe: extinction phenomenon, contralateral
homonymous field defects and hemisensory loss. There
may be apraxia, agnosia and dysphasia/aphasia if the
dominant hemisphere is affected. Signs include ‘parietal
drift’ or falling of the outstretched contralateral arm,
astereognosis (inability to recognize an object placed in
the hand) and sensory inattention.
• Temporal lobe: problems with memory, comprehension,
emotion. Contralateral superior visual field defects,
complex hallucinations. There may be receptive aphasia
Table32.2 The origins of brain tumours
Site Example of tumour derived
Glia Astrocytomas (including
Meninges Meningiomas
Blood vessels Angiomas, angioblastomas
Schwann cells of the
cranial nerves
Pituitary gland Craniopharyngioma
Lymphocytes Primary CNS lymphoma
CNS, Central nervous system.
glioblastomas),
oligodendrogliomas,
ependymomas
Acoustic neuromas
(Wernicke aphasia, anomic aphasia), and word agnosia
if the dominant hemisphere is affected.
• Occipital lobe: homonymous hemianopia, visual
hallucinations.
• Cerebellopontine angle: vertigo and progressive
ipsilateral perceptive deafness (cranial nerve VIII),
numbness of the ipsilateral side of the face (cranial
nerve V), facial weakness (cranial nerve VII) and
ipsilateral cerebellar signs.
Raised intracranial pressure
Symptoms include headache (worse in the morning and
with stooping, coughing and sneezing), vomiting (possibly without nausea), papilloedema and ocular palsies.
Displacement of intracranial contents may cause focal signs
like direct mass effects or general effects due to herniation;
as this occurs there will be impairment of consciousness
progressing to coma and respiratory depression. ‘False localizing signs’ may be present (e.g. a lesion of cranial nerve
VI, as it is compressed against the petrous temporal bone).
Investigations
Diagnosis mainly relies on neuroimaging. MRI provides
more detailed images than CT. More advanced techniques
such as positron emission tomography, single photon emission CT, MR spectroscopy or MR angiography may provide additional information about the extent and grade of
the tumour; this is particularly useful in planning surgery.
If metastases are suspected, investigations for the primary
neoplasm should be performed. If a primary intracranial
tumour is suspected, stereotactic biopsy provides definitive
diagnosis of the type and grade of the tumour. It will also
rule out other causes, such as abscess or inflammatory lesions, which may be difficult to differentiate on imaging.
Management
Initial management is of the complications arising from the
physical presence of the tumour: dexamethasone for cerebral oedema and anticonvulsants for seizures. Emergency
surgery such as shunt insertion may be required to adequately decompress the brain.
Further treatment depends on the type and grade of the
tumour. Surgical resection is preferred if possible. External
beam radiotherapy can be curative. It is the treatment of
choice for secondary tumours. Whole brain radiotherapy
or involved-field radiotherapy (normal brain tissue exposed
to smaller amounts of radiation) is used for some types of
tumours, including medulloblastomas, oligodendrogliomas
and glioblastomas. Chemotherapy is used for CNS lymphomas. The benefits are limited for other types of tumours but
it is used as an adjunct to surgery and radiotherapy and in
palliative care.
A watch-and-wait policy is sometimes adopted for small,
indolent tumours such as low-grade meningiomas.
290
Movement disorders
3232
MOVEMENT DISORDERS
Parkinsonism
Parkinsonism is a syndrome of tremor at rest, rigidity,
bradykinesia and later, postural instability; it has several
causes. The differential diagnosis is detailed in Table32.3.
This section will focus on Parkinson disease (PD), which is
the idiopathic syndrome of parkinsonism.
First described by James Parkinson in 1817, PD is due
to degeneration primarily affecting dopaminergic neurones
of the zona compacta of the substantia nigra. Eosinophilic
inclusion bodies (Lewy bodies) are characteristic pathological features of this progressive neurodegenerative disorder.
The incidence increases with age; an estimated 100–180
people per 100,000 are affected. It is more common in males.
COMMUNICATION
It is essential to have a holistic approach to
the care of patients and their carers in chronic
conditions such as Parkinson disease. As such, a
multidisciplinary approach, involving geriatricians,
Parkinson disease specialists, GPs, hospital
and community nursing staff, pharmacists,
physiotherapists, occupational therapists and
instituted. This hopefully culminates in the
formation of a supportive therapeutic alliance.
Clinical features
Early in the progression of PD the patient may report fatigue, muscular discomfort or restlessness. Fine movements
may be difficult. Onset is unilateral, becoming bilateral after
months or years, although severity may remain asymmetric
for the duration of the disease. Muscle power and tendon
reflexes are usually normal.
Tremor
Initially, this is intermittent and may appear only when the
patient is tired. The frequency of the tremor is 4–6 Hz and
the tremor is most marked at rest (whereas a cerebellar
tremor is more marked on intention). There is a ‘pill rolling’
movement of the thumb over the fingers.
Rigidity
There is resistance to passive movement, which may be
smooth throughout its range (‘lead pipe’ rigidity). When
combined with tremor, resistance to passive movement is
jerky and is termed ‘cogwheel’ rigidity. It is likely that rigidity contributes to the features of stooped posture and reduced arm swing that are commonly seen in PD (Fig.32.2).
Bradykinesia
‘Bradykinesia’ means difficulty in initiating movements.
Dexterity is often affected first, and it may be difficult for
the patient to rise from a chair. Writing becomes small (micrographia), spidery and cramped. Repeated movements
show slowing and reduced amplitude. The face is expressionless and mask-like, the frequency of spontaneous blinking reduces and the voice is monotonous and unmodulated.
There is reduced arm swing while walking and a shuffling,
festinant gait with unsteadiness on turning (gait freezing
may occur).
Table32.3 Differential diagnosis of parkinsonism
Differential diagnosis Suggestive features
Idiopathic Parkinson disease Asymmetry of onset, not ascribable to other cause
Parkinson plus syndromes Progressive supranuclear palsy Supranuclear ophthalmoplegia, pseudobulbar palsy,
Multisystem atrophy Autonomic dysfunction, parkinsonism, cerebellar or
Dementia with Lewy bodies Dementia preceding or simultaneous to movement
Drug-induced parkinsonism Neuroleptics, antiemetics,
antipsychotics, MPTP
Vascular parkinsonism History of vascular disease, evidence on CT scan
Metabolic disorders Wilson disease,
neuroacanthocytosis
Postinfectious Encephalitis lethargica Preceding episode of illness
Toxic Heavy metals, carbon monoxide Known history of exposure, often occupational
MPTP, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
postural instability, cognitive impairment. Rigidity
and bradykinesia are symmetrical in onset
pyramidal involvement. Symmetrical in onset
disorder
Relieved by removal of causative agent
Young age at onset, features on laboratory
investigation
291
Nervous system
Fig.32.2 Typical posture in Parkinson disease. (Courtesy
Dr Kamal, St George's Hospital, Lincoln.)
HINTS AND TIPS
To examine a patient for bradykinesia, ask the
patient to unbutton and button his or her shirt.
Other features
Postural instability occurs late in the disease and results
in a significant risk of falls and serious injury. Disordered
swallowing causes saliva to gather and drip from the halfopen mouth. Autonomic dysfunction is common and
may cause constipation and urinary difficulties. Rigidity
may be accompanied by pain and sensory disturbance.
Dementia may occur. It is characterized by the presence of
visual hallucinations and frequent fluctuations in lucidity.
Sleep disorders and mood disorders such as depression are
frequently seen.
CLINICAL NOTES
DIAGNOSING PARKINSON DISEASE
The diagnosis of Parkinson disease is clinical.
Laboratory investigations may help exclude
metabolic causes if there is a degree of suspicion.
In difficult cases, single photon emission CT
scanning with radioactive iodine may help.
Management
The disease is treated symptomatically. Physiotherapy can
improve the gait and help build confidence. Physical aids
such as high chairs and rails may help with daily activities.
Patients should have access to occupational therapy and
speech and language therapy. Patient and carer information,
education and support are very important.
Drug therapy
The aim of drug therapy is to correct the neurochemical
imbalance. This may greatly improve the quality of life but
does not prevent progression of the disease, and 10%–20%
of patients are unresponsive to treatment.
Treatment is started at low doses and increased in
small increments. Common side effects include motor
complications (young patients more often affected) and
neuropsychiatric complications (older patients more often
affected).
Levodopa—Levodopa (-DOPA), the most effective
agent in PD, acts mainly by replenishing depleted striatal
dopamine. It helps reduce bradykinesia and rigidity more
than tremor. It is administered with a peripheral dopa
decarboxylase inhibitor (e.g. benserazide or carbidopa),
which prevents the peripheral breakdown of -DOPA to
dopamine but, unlike -DOPA, does not cross the blood–
brain barrier. Effective brain concentrations of dopamine
can thus be achieved with lower doses of -DOPA.
The reduced peripheral formation of dopamine decreases peripheral side effects (e.g. nausea, vomiting and
cardiovascular effects). Domperidone (a peripherally selective dopamine D2 receptor antagonist) is used to help
treat nausea and vomiting. Late complications of -DOPA
use include sudden unpredictable swings of the ‘on–off’
syndrome, dyskinesia and ‘end-of-dose’ deterioration. In
the latter example, the duration of benefit after each dose
becomes progressively shorter. This may be increased with
modified-release preparations.
Dopamine agonists—These act at the endogenous neuroreceptor, and are effective in treating motor features of
the disease. They may be used as an adjunctive therapy or
a monotherapy. Dopamine agonists are less effective than
-DOPA.
The most common side effects are nausea due to stimulation of the area postrema in the medulla (can be alleviated
292
Movement disorders
3232
with domperidone) and dyskinesias. Drugs in this group
include bromocriptine, cabergoline, ropinirole, rotigotine
and apomorphine (which may be given by an injection or
continuous subcutaneous infusion).
Monoamine oxidase B inhibitors—Selegiline and
rasagiline inhibit the breakdown of dopamine and offer
modest symptom control. They are licensed as first-line
therapy but are more often used as an adjunct. Safinamide
is a new monoamine oxidase B inhibitor that has recently
been licensed in the United Kingdom as an adjunct for
treatment of mid- to late-stage PD in patients who are experiencing motor fluctuations.
Catechol O-methyltransferase inhibitors—These reduce the peripheral breakdown of -DOPA and thus reduce
the fluctuation in plasma levels and prolong the benefit
from each dose. Entacapone is an example.
Anticholinergics—Examples include benzhexol and
procyclidine. Tremor and rigidity are reduced more than
akinesia. They are best avoided in the elderly because of
their side effects, and are not recommended as first-line
therapy.
Amantadine—The mechanism of action of this drug
is unclear. It reduces bradykinesia and rigidity more than
tremor. It may be helpful in the late stages of disease as an
adjunct. It is not recommended as first-line therapy.
Other therapy
Surgery to alter brain regions affected by PD (subthalamotomy, thalamotomy or pallidotomy) may be considered
in patients with poor response to medication/intolerable
side effects, or those with severe fluctuations in response
to drugs (on–off syndrome). This may involve destruction
of parts of these nuclei or implantation of electrodes to
enable electrical stimulation (thalamic, pallidal or subthalamic deep brain stimulation). There is no good evidence
currently for the transplantation of dopaminergic neurones,
nor for gene therapy or nerve factor infusion.
Tremor
Tremor is defined as a rhythmic oscillatory movement of
a body part, most commonly the hands. It results from the
contraction of opposing muscle groups and may be a sign
or a symptom of the underlying disease. In evaluation of
a tremor, important points to consider are the frequency
and amplitude, when it is present or most pronounced (at
rest, on action or in fixed posture), how disabling it is and
whether the patient has symptoms or signs suggestive of
a clear underlying disorder. The differential diagnosis of
tremor is summarized in Table32.4.
Essential tremor
This is most common type of tremor. Usually it is of variable amplitude and rapid frequency (4–12 Hz). The hands
are most commonly affected (but the head, trunk or legs
can be involved). It is a postural tremor that is maintained
Table32.4 Causes of tremor
Type Features Causes
Resting Seen when patient
Postural Seen when the
Intention (also
known as
‘cerebellar
tremor’)
is relaxed with
hands at rest
muscles are
working against
gravity when, e.g.
hands are held
outstretched
Anxiety
Thyrotoxicosis
Physiological
Seen during
voluntary active
movement, when,
e.g. patients
try to touch the
examiner's finger
with their own
finger
Parkinsonism
Essential tremor
tremor – often
enhanced by
adrenergic
agonists
Cerebellar disease
Midbrain lesions
on movement and can be severely disabling. It does not
occur during sleep. Classically it is alleviated by alcohol,
but this is an inadvisable treatment. Some patients will
respond to β-blockers (propranolol). Botulinum toxin A
injections can be helpful in treating head tremor. In severe
intractable cases, thalamotomy or deep brain stimulation
is sometimes used.
Cerebellar tremor
This is classically a coarse low-frequency (<5 Hz) intention tremor. The amplitude increases as the movement approaches its end point. Tremor is usually perpendicular to
the direction of movement. It is caused by dysfunction of
the cerebellum or its outflow. Other features of cerebellar
disease may be present (see Chapter22).
Huntington Disease
This is an autosomal dominant inherited disorder caused by
an abnormal expansion (>35 repeats) of a normal repetitive
cytosine–guanine–thymine (CAG) sequence at the start of
the gene on chromosome band 4p16.3 which encodes the
protein huntingtin. The mutation causes a progressive neurodegenerative disease characterized by chorea (irregular,
involuntary, ‘dance-like’ movement), dystonia, behavioural
problems and cognitive decline. It usually starts in middle
age, although earlier onset and more severe disease may be
seen with successive generations: this is termed ‘anticipation’.
293
Nervous system
Neuroleptics, benzodiazepines or tetrabenazine (dopamine
depleting drug) may help control chorea, but there is no
disease-modifying or curative treatment.
Sydenham chorea
This is a neurological manifestation that occurs weeks to
months after group A streptococcal infection and is one of
the features of acute rheumatic fever. Clinical features include involuntary movements, hypotonia and weakness. It
is usually self-limiting.
Other movement disorders
For a description of dystonias, tics, myoclonus and akathisia, see Crash Course: Neurology.
MULTIPLE SCLEROSIS
General overview
MS is an autoimmune, inflammatory, demyelinating disorder. It is the most common cause of neurological disability
in young adults in the United Kingdom. The prevalence of
MS differs worldwide. Females are much more commonly
affected. The cause of the disease is unknown. It is thought
that environmental factors trigger the condition in genetically predisposed individuals. Abnormal immune response
to viral infections (e.g. Epstein–Barr virus) has been suggested as one of the possible causes. Relapsing/remitting MS
has an average onset of 25–29years, whereas the onset of
primary progressive MS is around a decade later.
Pathogenesis
The hallmark of MS is the presence of multiple lesions in
the CNS (not peripheral nerves) disseminated in location
and time. The pathogenesis is not fully understood, but inflammation, demyelination and axonal loss all play a role. It
is thought that the disease is started by self-reactive lymphocytes which invade the CNS, causing blood–brain barrier
disruption and areas of inflammation and demyelination.
Over time, repeated insults lead to sustained activation of
microglia (resident macrophages of the CNS), which results
in axonal loss. Sites of predilection include the optic nerve,
spinal cord, periventricular areas and brainstem.
Clinical features
There is a wide spectrum of disease activity, and the course
of the condition is extremely variable. It is divided into the
following subtypes:
• Relapsing–remitting MS is present in 85% of patients.
Here, symptom-free periods are followed by relapse.
A small number of patients experience progression
between relapses (‘relapsing progressive’ MS)
• Secondary progressive MS: two-thirds of all
relapsing–remitting patients will enter a ‘secondary
progressive’ phase.
• Primary progressive MS: progressive disease from the
outset. This occurs in about 15% of patients.
The onset is monosymptomatic in 85% of patients.
Common presentations include optic neuritis, symptoms
referable to the brainstem and cerebellum (including diplopia and ataxia) or sensory disturbance of the limbs and
leg weakness.
Progression of MS is very variable and depends on the
pattern of disease. The relapsing–remitting type has a better prognosis. One-quarter of patients have a nondisabling
form of the disease.
Optic neuritis
This presents as unilateral eye pain (often exacerbated by eye
movement) and/or loss or reduction of vision. Central vision
is usually more severely affected, with scotomata developing,
but complete uniocular blindness may occur. The optic nerve
head appears normal unless the lesion is very anterior, when
the disc may be swollen. In 90% of patients, vision improves
over a few months, but colour vision may be permanently
affected. Transient blurring of vision lasting minutes, associated with exercise or raised body temperature, may occur
(an example of Uhthoff phenomenon—worsening of symptoms with increased temperature). Following an episode of
optic neuritis, optic atrophy may ensue with pallor of the disc
on funduscopic examination. The risk of MS following optic
neuritis depends on whether lesions are present on MRI.
Diplopia
This is a common symptom caused by brainstem lesions involving fibres of cranial nerve III, IV, or VI, or by lesions in
the medial longitudinal fasciculus causing an internuclear
ophthalmoplegia (see Chapter2).
Sensory symptoms
Ascending sensory symptoms are very common.
Paraesthesia and dysaesthesia (altered sensation), diminished proprioception and vibration sense, and reduced pain
and light touch sensation may all be present. The distribution differs; it can be limited to the extremities, patchy over
the limbs and trunk or present in an ‘evolving sensory level’
pattern. Flexion of the neck may lead to an electric shock
sensation in the back and limbs (Lhermitte sign), which is
associated with a lesion in the cervical cord.
Motor weakness
Lesions of the spinal tracts may cause ascending weakness
and spasticity in the limbs. The lower limbs are often more
affected than the upper limbs. Upper motor neurone signs
are present.
294
Multiple sclerosis
3232
Cerebellar signs
Cerebellar signs include nystagmus, incoordination, tremor,
dysdiadochokinesia, titubation (continuous rhythmical
tremor of the head and trunk) and dysarthria.
HINTS AND TIPS
Cerebellar lesions can be remembered with
the mnemonic DASHING: dysdiadochokinesia,
ataxia, speech abnormalities (fluctuating, slurring),
hypotonic reflexes, intention tremor, nystagmus,
and gait abnormalities.
Other manifestations
Other manifestations include:
• Cognitive impairment: especially of memory, sustained
concentration and abstract conceptual reasoning.
• Psychiatric abnormalities: depression, psychoses,
euphoria may be present in severely disabled patients.
• Pain: most commonly neuropathic or musculoskeletal in
origin; trigeminal neuralgia is 300 times more common
in patients with MS than in the general population.
• Paroxysmal symptoms: these include tonic seizures
and rapid flickering contraction in the facial muscles
(myokymia). Myokymia may frequently occur in
healthy people and is not necessarily pathological.
• Autonomic symptoms: urinary frequency, urgency,
incontinence; constipation or faecal incontinence;
sexual dysfunction; thermoregulatory dysfunction.
• Uncommon manifestations: ‘useless hand’ syndrome
(an upper limb ataxia), lower motor neurone
signs, swallowing and respiratory problems, and
extrapyramidal movement disorders.
Investigations
The diagnosis of MS is made by a consultant neurologist
based on established criteria, such as the revised 2010
McDonald criteria (see Further reading). There must be
evidence of lesions disseminated in space and time. MRI
is used to support the diagnosis (see later). Alternative diagnoses should be excluded (see clinical notes: differential
diagnosis of myltiple sclerosis).
CLINICAL NOTES
DIFFERENTIAL DIAGNOSIS OF MULTIPLE
SCLEROSIS
• A single episode of disease consistent with
multiple sclerosis is termed ‘clinically isolated
syndrome’—other diagnosis must be excluded.
• Inflammatory conditions: primary angiitis of
the central nervous system, systemic lupus
erythematosus (SLE), primary Sjögren syndrome,
Behçet disease and polyarteritis nodosa (PAN), and
in children acute disseminated encephalomyelitis.
• Infectious diseases: Lyme disease, brucellosis,
tuberculosis, human T-lymphotropic virus type
1-associated myelopathy, HIV infection.
• Granulomatous disorders: sarcoidosis and
granulomatosis with polyangiitis.
• Multiple emboli.
• Other: neuromyelitis optica (previously
known as ‘Devic disease’) involves extensive
demyelination of the spinal cord and optic
nerve and is more common in African and
Asian populations. Familial conditions include
adrenoleucodystrophy and cerebral autosomal
dominant arteriopathy with subcortical infarcts
and leucoencephalopathy (CADASIL).
The following investigations are important in a patient with MS:
• MRI shows lesions in the vast majority of patients with
clinically definite disease.
• The CSF shows lymphocytosis and moderately raised
protein level. Oligoclonal bands of immunoglobulin G
(IgG) isolated to the CSF are seen in 90% of patients
with clinically definite MS but are not specific for MS.
• Delay in the visually evoked potentials can signify early
demyelination in otherwise asymptomatic patients.
Delays may also occur in auditory or somatosensory
evoked potentials depending on the site of the lesions.
• Antibodies to myelin proteins may be present but are of
no diagnostic use. Antibodies to aquaporin 4 are 98%
specific for neuromyelitis optica.
Management
Treatment of MS has two aims: symptom management and
disease modification. Pulses of IV methylprednisolone effectively shorten acute relapses but do not alter the course of the
disease and should be used sparingly to limit side effects.
Symptomatic treatment is of great importance.
Physiotherapy and occupational therapy maintain maximum function. Fatigue can be reduced with amantadine.
Spasticity may respond to baclofen and/or gabapentin; tizanidine and vigabatrin are alternatives. Bladder symptoms
can be managed with convene drains, pads or intermittent
self-catheterization. Anticholinergic agents (e.g. oxybutynin) may reduce urinary frequency. In men with erectile
dysfunction, sildenafil may be helpful.
Several disease-modifying agents have shown promise in reducing the frequency of relapses and lesions on MRI. However,
295
Nervous system
whether this translates into a reduction in the accumulation
of disability and a delay in disease progression is unclear. Beta
interferons and glatiramer acetate remain first-line therapy for
relapsing- remitting disease. Fingolimod (immunomodulator)
is recommended for treatment if no improvement is observed
despite beta interferon therapy. Alemtuzumab (monoclonal antibody that mediates death of B and T cells) is recommended for
treatment of active relapsing remitting disease. Teriflunomide
and daclizumab are alternatives. Antiinflammatory dimethyl
fumarate can be used in active relapsing–remitting disease.
Natalizumab (monoclonal antibody against α4 integrin) is reserved for patients with rapidly evolving relapsing–remitting
disease because the severe side-effect profile, including progressive multifocal leucoencephalopathy. Several other agents are
being assessed in clinical trials.
HINTS AND TIPS
Live vaccinations may be contraindicated in
patients treated with disease-modifying drugs.
CENTRAL NERVOUS SYSTEM INFECTION
Meningitis
General overview
Meningitis is inflammation of the meninges. It may be
caused by:
• infection: bacteria, viruses, fungi, parasites;
• malignant cells;
• blood (e.g. following SAH);
• inflammatory conditions: sarcoidosis, SLE, vasculitis;
• air, drugs or contrast media during encephalography.
The term ‘meningitis’ is usually reserved for infection
of the meninges by organisms. Viral meningitis is the most
common cause, however, the disease is usually mild and
self-limiting. Bacterial meningitis is a life-threatening condition that is associated with high morbidity and mortality.
This section will focus on bacterial meningitis.
• in older adults: as for young adults but prone to S.
pneumoniae;
• in immunocompromised patients and the elderly:
prone to pneumococcus, Listeria, gram-negative
organisms, Cryptococcus, Mycobacterium tuberculosis.
Vaccination against H. influenzae type b, serogroup B and
C meningococcus and some types of pneumococcus has reduced the incidence of infections significantly.
Clinical features
Meningism
The features of meningism include headache, neck stiffness, back rigidity, photophobia and headache. Kernig sign
(Fig.32.3) (i.e. pain and resistance on passively extending
the knee with the hips fully flexed) or Brudzinski sign (head
flexion elicits hip flexion) may be positive.
Sepsis
High temperature is typical. The patient may describe
malaise and arthralgia. Any rash may occur, although a
petechial/purpuric rash is strongly suggestive of meningococcal disease. Rigors, tachycardia and hypotension
may occur.
Raised intracranial pressure
Headache, vomiting, altered mental state and seizures may
all occur. Bradycardia with hypertension (Cushing reflex)
can occur.
In tuberculous meningitis, symptoms may initially
be nonspecific with malaise, anorexia, headache and
mild pyrexia. Symptoms may persist for days, but gradually an unremitting deterioration occurs. There may
be personality changes and intermittent dulling of consciousness before signs of meningism are obvious. The
appearance of focal neurological signs suggests a complication (e.g. venous sinus thrombosis, cerebral oedema or
hydrocephalus).
Causative organisms
The causative organism is likely to differ with the patient's age:
• in neonates (patients younger than 28days):
Streptococcus agalactiae (group B streptococcus),
Escherichia coli, Streptococcus pneumoniae and Listeria
monocytogenes;
• in children: meningococcus (Neisseria meningitidis), S.
pneumonia, Haemophilus influenzae type b;
• in young adults: S. pneumoniae, H influenzae type b,
meningococcus, streptococci, staphylococci, gramnegative bacilli;
296
Fig.32.3 Eliciting Kernig sign.
Central nervous system infection
3232
Investigations
HINTS AND TIPS
Do not delay therapy in favour of completing
investigations in suspected meningitis.
• Blood: full blood count, urea and electrolytes,
C-reactive protein, glucose, coagulation screen,
blood cultures, whole-blood polymerase chain
reaction (PCR) for Neisseria meningitides, arterial
blood gas.
• Lumbar puncture: performed urgently once
raised intracranial pressure has been excluded.
cerebrospinal fluid (CSF) is sent for Gram stain,
Ziehl–Neelsen stain (for tuberculosis), culture,
microbiology, sensitivity testing, cytology, virology,
glucose measurement, protein measurement, rapid
antigen screen for PCR, and occasionally India ink
stain for cryptococci. CSF changes in meningitis
are summarized in Table32.5 (see also Chapter22).
Management
When meningitis is suspected, antimicrobials should be administered immediately. If a lumbar puncture can be performed quickly, it may be possible to obtain a sample of CSF
first, but this should not delay the administration of antibiotics.
In an out-of-hospital setting, give benzylpenicillin intramuscularly/IV. Hospital treatment is usually empirical initially (consult local policy) (e.g. IV ceftriaxone for patients
younger than 50years and IV ceftriaxone and amoxicillin (to
cover Listeria) in patients older than 50years). IV Aciclovir
should also be given if a viral cause is suspected. Targeted
therapy is started once the causative organism is known.
Supportive measures include analgesia, antiemetics,
IV fluids and nutritional support. Manage any complications, including seizures, disseminated intravascular coagulation and pericardial effusion, reactively. If meningitic
signs predominate, or bacterial meningitis is suspected or
confirmed, give IV dexamethasone as soon as possible. It
is also indicated in tuberculous meningitis. It should be
avoided in septic shock, known meningococcal disease and
immunocompromised states.
Meningitis is a notifiable disease, and cases must be
reported to the Department of Health and Social Care.
Prophylactic antibiotics are recommended for close contacts of the index case.
Encephalitis
This is inflammation of the brain parenchyma. There is usually
some inflammation of the meninges in encephalitis and conversely some inflammation of the parenchyma in meningitis.
Viruses are the most common cause of encephalitis, with
herpes simplex virus being the main pathogen. Bacteria
(e.g. Listeria, Mycobacterium tuberculosis), fungi (e.g.
cryptococcosis), parasites (e.g. toxoplasmosis, especially in
the immunocompromised; schistosomiasis), toxins or autoimmune disorders can also lead to the condition.
The classic triad of acute encephalitis is altered mental
state, headache and fever, but most patients present with
features of meningitis (see earlier).
CLINICAL NOTES
ENCEPHALITIS
Subacute sclerosing panencephalitis is a late
complication of measles that develops, on
average, 6–15years after the primary infection.
The condition has very high morbidity and
mortality, and there is currently no cure.
The diagnosis depends on knowledge of local
epidemics, unreliable radiological features (such
as temporal lobe swelling in herpes simplex
virus (HSV) encephalitis) and EEG findings
(periodic complexes in HSV encephalitis), CSF
findings (see Chapter22) and demonstration of
viruses in the CSF by serology or PCR. Often, it
is a presumptive diagnosis.
HSV encephalitis is potentially treatable, and therefore
if there is any suspicion of encephalitis aciclovir
should be given intravenously (in addition to other
empirical treatments for meningoencephalitis), and
the CSF should be sent for HSV PCR.
Table32.5 Changes in the cerebrospinal fluid in meningitis
Normal Viral Bacterial Tuberculous
Appearance Clear Clear/turbid Turbid Turbid/fibrinous
Predominant cell <5 mononuclear cells
per mL
Protein (g/L) 0.2–0.4 0.4–0.8 0.5–5 0.5–5
Glucose More than two-thirds of
plasma level
10–100 mononuclear
cells per mL
More than two-thirds
plasma level
200–3000 polymorphs
per mL
Less than two-thirds
plasma level
10–300 mononuclear cells
per mL
0–300 polymorphs per mL
Less than two-thirds of
plasma level
297