Neurology - Multiple sclerosis Flashcards
Definition of MS
MS is a demyelinating disease characterised by episodes of neurological deficit appearing irregularly throughout the CNS both in anatomical site and time.
Thus, one episode of demyelination is insufficient to diagnose MS.
Epidemiology of MS
UK prevalence is estimated at 1:1000
Woman are slightly more affected than men
First episodes usually occur in young adulthood, with a peak at around 30 years.
What is the aetiology of MS?
Currently unknown.
Favoured hypothesis is that an environmental trigger (e.g. viral infection) triggers demyelination in a genetically susceptible individual.
Presence of chronic inflammatory cells in active plaques and linkage to certain HLA genotypes suggests an immune basis for the disease.
MHC linkage together with the observation that MS is more common in monozygotic cf. dizygotic twins suggests a genetic component.
What are the pathological features of MS?
Patches of demyelination occur in discrete areas (plaques) in the white matter of the CNS with relative axonal sparing - the PNS is not affected.
These plaques tend to occur close to veins.
They are especially common in:
- Optic nerves
- Brainstem
- Cerebellar peduncles
- Dorsal and pyramidal (lateral) tracts
What is the difference between an acute and a chronic plaque?
Acute plaques are soft and pink with ill defined boundaries. Histologically there is myelin breakdown and phagocytosis by macrophages. Perivascular cuffing (regions of leucocyte aggregation) with inflammatory cells (plasma and T cells) is common in the acute plaque. Plasma cells synthesise immunoglobulin.
Chronic plaques consist of sharply defined areas of myelin loss and few if any oligodendrocytes. As myelin breaks down, reactive gliosis occurs. Inflammatory infiltrate subsides leaving only a small number of perivascular lymphocytes.
How does demyelination in MS affect neuronal function?
Demyelination leads to a reduction in axonal conduction velocity, with initial distortion followed by loss of impulse conduction. Oedema around acute lesions contributes to the neurological deficit.
Symptoms of MS
Visual disturbance, clumsiness, weakness (UMN), numbness (sensory deficit), intention tremor (cerebellar signs), cognitive impairment, bowel or bladder dysfunction and sexual dysfunction.
Symptoms are commonly made worse by heat and exertion (Uhthoff phenomenon).
What visual disturbances occur in MS?
Optic neuritis is a common presenting feature. Symptoms include pain around one eye (exacerbated by movement) blurred vision and loss of colour vision.
On examination, visual acuity/ colour vision are reduced with a relative afferent pupillary defect. There may be a field defect (typically central scotoma) and the optic disc is pink and swollen.
Diplopia with internuclear ophthalmoplegia may occur.
How does MS progress?
Symptoms of MS typically evolve over days - weeks, reach a plateau and gradually resolve (partially or completely) over weeks or months.
Recurrences are unpredictable and may affect the same or different parts of the CNS. There are no clearly identified precipitating factors, although intercurrent illness and pregnancy have been implicated.
What are the four main patterns of disease in MS?
1) Relapsing-remitting (80% of cases) - initial episodes may resolve completely or nearly so. Subsequent episodes usually result in some residual disability, with patients eventually progressing to the secondary progressive form
2) Secondary progressive - steady progression without remission
3) Primary progressive - no clear cut relapses or remissions; more common in those presenting in middle age with a spastic paraparesis
4) Progressive - relapsing - (rare) variable history. Some patients have years between relapses while others experience a debilitating progressive deterioration from an early stage
How is MS diagnosed?
Diagnosis is clinical using McDonald criteria.
Requires at least 2 episodes of neurological dysfunction separated in time and space.
- Visual evoked potentials (VEP): demyelination causes an abnormality (usually delay) in occipital EEG tracings in response to stimulus presented to the eyes. Present in 95% of MS patients but not specific
- Lumbar puncture: lymphocytosis and raised protein in the presence of active disease; CSF immunoelectrophoresis shows increased proportion of IgG and oligoclonal bands
- MRI: plaques of demyelination appear as bright lesions and clinically silent lesions are frequently revealed.
What is the differential diagnosis for MS?
For relapsing remitting disease:
- TIA
- SLE
- sarcoidosis
For primary progressive disease:
- other causes of spastic paraparesis
- MND
- spinal/ cerebellar degenerative diseases
Outline the management of MS
Physiotherapy, rehabilitation, medical therapy, surgery and psychology all have a role. Treatment is aimed at:
- management of an acute relapse
- modifying the course of the disease
- symptom control
How is an acute relapse of MS managed?
High dose corticosteroids (e.g. IV prednisolone) may improve the speed of recovery during acute exacerbations
What interferon is used as a disease modifying agent in MS?
Interferon beta - 2 forms available:
- interferon beta 1a (identical to its natural counterpart)
- interferon beta 1b (has a single amino acid substitution)
Interferon beta is primarily used for relapsing remitting disease but not all patients respond. Results of clinical trials have shown varying efficacy, but in general there is a one-third reduction in relapse frequency and a small slowing in the rate of progression.
Glatiramer
= immunomodulating agent, reduces relapses and MRI abnormalities in patients with relapsing-remitting disease
What biological agents are used as disease modifying agents in MS?
Natalizumab = monoclonal antibody that inhibits leucocyte migration into the CNS, is an option for the treatment of adults with highly active relapsing remitting MS that has not responded to other disease modifying agents.
Its more widespread use is limited due to an increased risk of opportunistic infections and the potentially fatal side effect of progressive multifocal leucoencephalopathy.
Alemtuzamab = monoclonal antibody targeting CD52 on the surface of mature lymphocytes, is the subject of ongoing clinical trials but shows promise in relapsing remitting disease.
What symptom control may patients with MS require?
- weakness: physic and rehab
- spasticity: may respond to stretching exercises, antispasmodics (e.g. BDZs or baclofen), dantrolene acts directly on skeletal muscle to reduce spasm, botulinum toxin, surgery
- bladder dysfunction: antimuscarinic agents increase bladder capacity, alpha adrenoceptor blockers, self catheterisation
- sexual dysfunction: oral PDE type 5 inhibitors, intracavernosal injections of papaverine
- psychology
What is the prognosis of MS?
Average life expectancy after the onset of symptoms is 20-30 years. Overall, 80% of patients experience steadily progressive disability, 15% follow a fairly benign course, and 5% die within 5 years.
Patients whose disease onset is sensory tend to have a better prognosis.
Poor prognostic factors are:
- older age at onset
- early cerebellar involvement
- loss of mental acuity
What is neuromyelitis optica?
This presents as an attack of optic neuritis with “longitudinally extensive transverse myelitis”. Each can occur in isolation giving rise to the concept of NMO spectrum.
NMO was thought to be a variant of MS but is now recognised as a specific disease entity caused by antibodies to aquaporin 4. This causes a distinct pathology of complement mediated destruction and perivascular astrocytosis.
What are the leucodystrophies?
These are a miscellaneous demyelinating condition. Most of the leucodystrophies result from a failure to synthesis normal CNS myelin.
2 of these disorders are due to inherited lysosomal enzyme deficiencies and can be diagnosed antenatally. They are metachromatic leucodystrophy and Krabbe’s globoid cell leucodystrophy.
