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QuestionChoice
Anti-aquaporin 4 (AQP4) antibodies are specific for neuromyelitis optica spectrum disorders (NMOSD). Testing would be recommended in patients with long segments of spinal cord demyelination with or without optic neuritis, and in patients with recurrent optic neuritis with normal brain imaging
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Testing for anti-aquaporin 4 (AQP4) antibodies
QuestionChoice
While B12 deficiency can lead to neurological signs, it would not lead to abnormal findings on MRI, nor would symptoms resolve as spontaneously and rapidly
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B12 level
QuestionChoice
Whilst fundoscopy should be considered in any patient with a new visual deficit, it would be unlikely to lead to a definitive diagnosis in the context of a history suggesting MS, with an abnormal MRI. Fundoscopy is likely to be normal in MS
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Fundoscopy
QuestionChoice
This patient has a history suggestive of multiple sclerosis, clinically isolated neurological deficits separated in time. The MRI confirmed several hyperintensities in the periventricular white matter. The next investigation is CSF examination, looking for the typical finding of oligoclonal bands, the presence of which gives a definitive diagnosis of MS
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Lumbar puncture looking for oligoclonal IgG bands in the cerebrospinal fluid (CSF)
QuestionChoice
This patient has already undergone an MRI which has demonstrated white matter lesions separated in space. A CT head is not likely to provide further information, nor a definitive diagnosis
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Computed tomography (CT) scan of the head
QuestionComment
Question: which investigation most likely to give definitive diagnosis.
Answer: CT head, goes onto explain why unnecessary test.
...?  
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# Summary

Multiple Sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system, characterised by the demyelination and axonal loss of neurons. Key symptoms include sensory disturbance, optic neuritis, internuclear ophthalmoplegia, cerebellar ataxia, and spastic paraparesis. Diagnosis largely involves the use of clinical history, MRI findings, and CSF analysis, aligning with the McDonald criteria. Management of MS involves both acute and chronic strategies, with glucocorticoids commonly used for acute attacks, and a combination of disease-modifying therapies (DMTs) and symptomatic treatments used in the long-term.

# Definition

Multiple sclerosis is a chronic autoimmune disease, primarily involving the central nervous system, which is marked by the degeneration of the insulating covers of nerve cells in the brain and spinal cord, leading to demyelination and eventual axonal loss.

# Epidemiology

MS predominantly affects females with a current ratio of 2.3:1 and a mean onset age of 30 years.

# Aetiology

The exact cause of multiple sclerosis remains unknown. However, a combination of genetic and environmental factors, including potential viral pathogens, are believed to be contributing factors. 

Pathologically, CD4-mediated destruction of oligodendroglial cells and a humoral response to myelin binding protein are key features of the disease.

# Signs and Symptoms

Multiple sclerosis can cause a wide range of symptoms depending on the affected area of the brain or spinal cord, but common presentations include:

- Sensory disturbance, marked by patchy paraesthesia
- Optic neuritis, characterised by loss of central vision, loss of red desaturation and painful eye movements
- Internuclear ophthalmoplegia, a lesion in the medial longitudinal fasciculus of the brainstem
- Subacute cerebellar ataxia
- Spastic paraparesis, as seen in transverse myelitis, including Lhermitte's sign.
- Bladder and bowel disturbance


# Classification

Multiple sclerosis may be divided into two groups:

- Relapsing-remitting (which may become secondarily progressive)
- Primary progressive.

Relapsing remitting MS makes up 80% of disease at presentation, compared with primary progressive which is <10%.

The remaining 10% fall into a difficult to classify intermediate group of progressive-relapsing disease.

# Differential Diagnosis

Diseases that should be considered in differential diagnosis include:

- **Neuromyelitis optica (Devic's disease)**: Characterised by optic neuritis and transverse myelitis.
- **Systemic lupus erythematosus (SLE)**: Presents with multisystem involvement, including the CNS. Symptoms may include fatigue, joint pain, rash, and fever.
- **Lyme Disease**: Early signs and symptoms include fever, chills, headache, fatigue, muscle and joint aches, and swollen lymph nodes. Later signs and symptoms may involve the nervous system.
- **Neurosarcoidosis**: Symptoms include seizures, hearing loss, facial palsy, and psychiatric symptoms.
- **Vitamin B12 Deficiency**: Presents with weakness, tiredness, or lightheadedness, heart palpitations and shortness of breath, pale skin, constipation, loss of appetite, nerve problems like numbness or tingling, and mental problems like depression, memory loss, or behavioral changes.


# Investigations

The diagnosis of multiple sclerosis is based on at least two of:

- Clinical history/examination
- Imaging findings
  - Typically these are periventricular white matter lesions seen on MRI **disseminated in time and space**

[lightgallery]

- Oligoclonal bands in the CSF
  - These reflect various immunoglobulins seen on CSF electrophoresis and indicate the presence of an auto-immune process in the CNS.
  - They are very sensitive for multiple sclerosis although they can also be found in other auto-immune and infectious conditions including Lyme disease, SLE and neurosarcoid.
 - Visual evoked potential can help further characterise the diagnosis in patients presenting with optic neuropathy

## McDonald criteria for Diagnosis

The McDonald criteria (last revised in 2017) is the generally accepted standard for diagnosis:

| Clinical Presentation                                        | Additional Data Needed                                       |
| ------------------------------------------------------------ | ------------------------------------------------------------ |
| 2 or more attacks (relapses) <br />2 or more objective clinical lesions | None; clinical evidence will suffice (additional evidence desirable but must be consistent with MS) |
| 2 or more attacks<br />1 objective clinical lesion           | Dissemination in space, demonstrated by:<br /> MRI _or_ <br />A positive (cerebrospinal fluid) CSF and 2 or more MRI lesions consistent with MS _or_ <br />Further clinical attack involving different site |
| 1 attack <br />2 or more objective clinical lesions          | Dissemination in time, demonstrated by: <br />MRI _or_ <br />Second clinical attack |
| 1 attack<br />1 objective clinical lesion (monosymptomatic presentation) | Dissemination in space demonstrated by: MRI or positive CSF and 2 or more MRI lesions consistent with MS **and** <br />Dissemination in time demonstrated by: MRI or second clinical attack |
| Insidious neurological progression suggestive of MS (primary progressive MS) | One year of disease progression (retrospectively or prospectively determined) and TWO of the following: <br />a. Positive brain MRI (nine T2 lesions or four or more T2 lesions with positive visual evoked potentials [VEP) <br />b. Positive spinal cord MRI (two focal T2 lesions) <br />c. Positive CSF |

# Acute management

- An acute attack of multiple sclerosis should be treated with glucocorticoids involving local neurology services
- 1g of intravenous methylprednisolone every 24 hours for 3 days is a typical regimen
- Infections must first be excluded
	- 	Always ensure to check routine bloods and urine dip to rule out any intercurrent infection.
	-  While these interventions does not appear to affect long term outcome, it does appear to reduce the duration and severity of individual attacks.


# Chronic management

Management of patients with multiple sclerosis should be led by a multidisciplinary team approach of neurologists, physiotherapists, occupational therapists, psychologists and many other allied healthcare professionals.

There are two groups of drugs used in the long term management of _relapsing remitting multiple sclerosis_: disease modifying therapies (DMTs) and symptomatic therapies.

The former group may be divided into three:

- First-line injectables such as beta-interferon and glatiramer
- New oral agents such as dimethyl fumarate, teriflunomide and fingolimod
- Biologics such as natalizumab and alemtuzumab.

As a general rule, increasingly effective treatments are associated with increasingly significant side effects.

The extent to which long-term use of DMTs reduces risk of secondary progressive MS is not yet clearly established.

Symptomatic therapies include:

- Physiotherapy
- Baclofen and Botox for spasticity
- Modafinil and exercise therapy for fatigue
- Anticholinergics for bladder dysfunction
- SSRIs for depression
- Sildenafil for erectile dysfunction
- Clonazepam for tremor

# Prognosis

The prognosis of multiple sclerosis (MS) can vary widely among individuals, and several risk factors have been identified that are associated with a worse prognosis. These risk factors may include:

1. **Age at onset**: Onset of MS at an older age, typically over 40, is associated with a worse prognosis.
2. **Male gender**: Men with MS often experience a more severe and rapidly progressing form of the disease compared to women.
3. **Primary Progressive MS**: This form of MS is characterised by a steady and continuous worsening of symptoms without distinct relapses and remissions. It tends to have a worse prognosis compared to relapsing forms of the disease.
4. **High relapse rate**: Frequent relapses and a higher relapse rate can indicate a more aggressive form of the disease, which may lead to greater disability over time.
5. **Rapid accumulation of disability**: A quick accumulation of physical disability in the early stages of the disease is associated with a less favorable prognosis.
7. **High lesion load**: A higher burden of lesions (plaques) in the brain and spinal cord on MRI scans is associated with a worse prognosis.
8. **Cognitive impairment**: Cognitive dysfunction, such as memory problems and difficulties with thinking and processing information, can indicate a worse prognosis.
10. **Comorbid conditions**: The presence of other medical conditions, such as depression or cardiovascular disease, can complicate the management of MS and lead to a worse prognosis.
11. **Smoking**: Smoking has been associated with an increased risk of developing MS and may also contribute to a worse prognosis.


It's important to note that while these risk factors are associated with a worse prognosis, the course of MS is highly variable, and individual experiences can differ significantly. Early diagnosis, appropriate treatment, lifestyle modifications, and a strong support system can help improve the prognosis and quality of life for people living with MS. 

# NICE Guidelines

[NICE Guidelines for Multiple Sclerosis](https://www.nice.org.uk/guidance/ng220)

[NICE CKS for Multiple Sclerosis](https://cks.nice.org.uk/topics/multiple-sclerosis/)
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Oligoclonal IgG bands in cerebrospinal fluid are a definitive diagnostic marker for multiple sclerosis.
A 29 year old female presents to the GP with a 5-day history of clouding of vision and difficulty differentiating colours. She has a past history of a 2-week period of left upper limb weakness that spontaneously resolved without intervention.

An MRI reveals several hyperintensities in the periventricular white matter at various regions.

What investigation is most likely to give a definitive diagnosis?
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