Description
Multiple Sclerosis (MS) is a chronic, immune-mediated demyelinating disorder of the central nervous system (CNS), characterised by inflammation, gliosis, and the formation of sclerotic plaques in the white and grey matter that are disseminated in time and place. The disease can be progressive or relapsing-remitting in nature, leading to a wide array of neurological deficits based on the location of the plaques.
Pathogenesis
MS is thought to arise from a complex interplay of genetic and environmental factors leading to autoimmune responses against CNS myelin. Immune cells, including T and B lymphocytes, infiltrate the CNS, causing inflammation and demyelination of neurons. This process results in the formation of sclerotic plaques which disrupts signal transmission, leading to the characteristic symptoms of MS.
Epidemiology, Risk Factors & Associations
- MS predominantly affects young adults aged between 20 and 50 years, with a mean age of onset around 30 years.
- The disease is more common in women, with a female-to-male ratio of approximately 3:1.
- Geographical variations are evident with a higher prevalence in regions further from the equator (110 per 100,000 population in northern Europe and North America).
Risk factors include:
- Genetic predisposition: Certain alleles of the human leukocyte antigen (HLA) system, particularly HLA-DR15 and HLA-DR2, are associated with an increased risk of MS.
- Viral infections: Exposure to the Epstein-Barr virus has been associated with a higher risk of MS.
- Smoking: Tobacco smoking is associated with a greater risk of developing MS and is linked to higher disease activity and progression.
- Vitamin D deficiency: Lower levels of vitamin D are associated with a higher risk of MS, which may explain the geographical distribution of the disease.
Clinical Features
Varies depending on the location of plaque formation and progression over time. Common clinical features include:
- Brainstem and cranial nerve involvement: Optic neuritis, internuclear ophthalmoplegia, trigeminal neuralgia, diplopia, vertigo.
- Cerebellum involvement: Ataxia, gait disturbance, oscillopsia.
- Cerebrum and spinal cord involvement: Limb sensory loss or paresthesias, upper motor neuron signs, transient electric shock sensation that extends down the spine and extremities upon flexion of the neck (Lhermitte sign), urinary incontinence.
- Others: Fatigue, depression, heat and exercise worsening symptoms (Uhthoff phenomenon), cognitive decline.
Complications
Common complications of MS include:
- Progressive disability with varying degrees of physical and cognitive disability can develop over time.
- Neuropsychiatric conditions such as depression, anxiety, and cognitive dysfunction.
- Spasticity and muscle weakness resulting in mobility problems and the need for assistive devices.
- Bladder and bowel dysfunction due to neurogenic bladder and bowel.
Subtypes
MS is classified into four patterns of longitudinal disease (based on disease progression and activity):
- Relapsing-Remitting MS (RRMS): Most common. Characterised by episodes of new or worsening symptoms (relapses) followed by periods of recovery (remissions).
- Primary Progressive MS (PPMS): Uncommon. Defined by progressively worsening neurologic function from the onset of symptoms.
- Secondary Progressive MS (SPMS): An initial relapsing-remitting course followed by progression of disability. About 85% of RRMS patients enter a secondary progressive phase.
- Progressive-Relapsing MS (PRMS): A steadily worsening disease from the onset with superimposed relapses.
Pathological Features
Histopathology
- Demyelination: Loss of myelin, the protective layer around neurons, is a hallmark of MS.
- Inflammation: Infiltration of immune cells like lymphocytes and macrophages.
- Gliosis: Scarring caused by an overgrowth of glial cells in response to inflammation.
- Axonal loss: Seen in chronic disease, leading to irreversible neurological deficits.
Biochemistry
- The presence of oligoclonal bands in cerebrospinal fluid (CSF) is a common finding but is not specific to MS.
Radiological Features
General Features
- Location: Periventricular white matter, corpus callosum, brain stem, cerebellum, spinal cord
- Morphology: Well-circumscribed areas (plaques) of demyelination.
- Optic neuritis most commonly affects the retrobulbar intraorbital segment of the optic nerve.1
- Brain atrophy (greater than normal ageing process) is an imaging hallmark, characterised by enlarged ventricles and reduced size of the corpus callosum.
- Cervical cord is the most commonly affected segment and the lesions usually extend over fewer than two vertebral segments in length.
- Spinal lesions tend to be multifocal. Enhancement suggests active disease.
- Focal lesions have an elongated configuration along the axis of the spinal cord and affect the peripheral part of the cord.
- Spinal cord atrophy, reflecting axonal loss, may also be observed
MRI
- T2/FLAIR:
- FLAIR more sensitive for detection of brain lesions (less reliable than STIR for spinal lesions).
- High-intensity lesions in typical location.
- Dawson’s fingers represent periventricular lesions extending perpendicular to lateral ventricles along the medullary venules.
- Ependymal dot-dash sign represents early perivenular involvement of the ependyma of the lateral ventricular roof. Appears as tiny dots and short dashes of FLAIR intensity.
- Acute lesions have surrounding high oedema
- Optic neuritis appears as optic nerve swelling (may persist permanently). Nerve atrophy suggests chronicity.
- Typical spinal cord lesions in MS are relatively, usually small and peripherally located (dorsolateral most common). They are most often found in the cervical cord and are usually less than two vertebral segments in length
- T1: Hypointense (black holes) indicating chronic areas of severe demyelination, axonal loss and irreversible clinical outcome.
- T1 C+:
- Enhancement in active lesions.
- Open-ring sign refers to the incomplete or open-ring pattern of enhancement, where the enhancing component is thought to represent the advancing front of demyelination (thus favours the white matter side of the lesion) and the open-ring segment is orientated towards the grey-matter.
- Optic neuritis demonstrates contrast enhancement.
- DWI/ADC: Active plaques may demonstrate restricted diffusion.
Grading and Staging
The Expanded Disability Status Scale (EDSS) is commonly used to quantify disability in MS, ranging from 0 (normal neurological examination) to 10 (death due to MS).
Diagnosis
Diagnosis of MS involves the following:
- Clinical criteria: The diagnosis is typically based on clinical findings and a history of symptoms suggestive of MS.
- MRI: Demonstrates evidence of lesions in at least two separate areas of the CNS and evidence of at least one lesion occurring at a different time.
- Lumbar puncture: May reveal oligoclonal bands in the CSF.
Differential Diagnosis
- Neuromyelitis Optica Spectrum Disorder: Involves optic neuritis and transverse myelitis, AQP4-IgG seropositive.
- Acute disseminated encephalomyelitis (ADEM): Often a monophasic disease, following viral infection or vaccination.
- Vitamin B12 deficiency: Can also cause subacute combined degeneration of the spinal cord.
- Lyme disease: May cause a similar clinical picture, particularly in endemic areas.
Management
- Disease-modifying therapies (DMTs): These are used to decrease the frequency and severity of relapses, slow the progression of disability, and limit new disease activity.
- Symptom management: This is tailored to the individual patient’s symptoms and may involve a multidisciplinary approach.
- Rehabilitation: Physical therapy, occupational therapy, and speech and language therapy can be beneficial.
- Neurology consultation: Patients with MS should be managed in conjunction with a neurologist.
While there is no cure for MS, appropriate management can significantly improve the quality of life and longevity for people with the disease.
References