11th August 2024

Multiple sclerosis and neuroinflammatory disorders

Overview of multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated demyelinating condition of the central nervous system, clinically defined as two or more episodes of neurological dysfunction affecting the brain, spinal cord or optic nerves separated in time and space. The hallmark of MS is symptomatic episodes of demyelination occurring months to years apart and affecting different anatomical locations.

The cause of MS is unknown, but it likely involves a combination of genetic factors, making some individuals more susceptible to the disease. Non-genetic triggers such as a preceding viral infection or low vitamin D levels can also cause an autoimmune response against myelinated axons in the CNS.  A characteristic feature of MS is the periventricular infiltration of lymphocytes and macrophages.

There is a marked geographic variation in the incidence of MS with the incidence being lower in equatorial regions, which supports the probability of an environmental trigger. MS classically presents in white women between the ages of 20 and 40.

Clinical features and diagnosis of multiple sclerosis

Symptoms of MS

The symptoms of MS vary and depend on the location of the demyelinating lesion. Common presentations of MS include optic neuritis, usually unilateral, and transverse myelitis. Individuals can also present with brainstem syndromes including internuclear ophthalmoplegia, cerebellar syndromes characterised by ataxia, and sensory syndromes. In addition, MS can present with symptoms of cognitive decline, depression or psychosis. As neural inflammation resolves and remyelination occurs there can be some recovery of function.

MS seems to be less active during pregnancy, especially in the last trimester, however many patients with MS have a relapse of symptoms within 3 months of delivery. MS does not affect fertility or increase the risk of miscarriage.

Uhthoff’s phenomenon is a transient worsening of symptoms when the body is overheated, such as in hot weather, during vigorous exercise or in a hot shower, and is often observed with MS.

Internuclear ophthalmoplegia (INO) is a gaze disorder where the affected eye shows impairment of adduction on conjugate lateral gaze. This is due to demyelination of the medial longitudinal fasciculus, a heavily myelinated tract connecting the oculomotor nucleus on the side of the lesion with the contralateral abducens nucleus. The commonest causes of INO are MS and brainstem infarcts.

Optic neuritis and MS

Optic neuritis is the first demyelinating event in 20% of patients who are diagnosed with MS. Approximately 40% of patients with MS experience optic neuritis at some point during their disease course.

Symptoms of optic neuritis include:

• Pain which is worsened by eye movement
• Temporary reduction in vision, the extent of which varies, and which can be permanent
• Visual field loss
• Loss of colour vision and colour perception
• Flashing lights, especially with eye movements
• Rapid afferent pupillary defect (RAPD), occurs due to asymmetrical disease of the optic nerve. The affected pupil will dilate to the light stimulus instead of constricting

A key differential for a RAPD is the Holmes-Adie pupil, which is often idiopathic but can be caused by a lesion in the efferent parasympathetic pathway. It is characterised by slow and incomplete constriction of the pupil to light, and, after the pupil has constricted, it remains so for a long time (tonic pupil). The full syndrome also includes an absence of deep tendon reflexes (although an abnormal pupil may be seen in isolation).

Diagnosis of MS

Diagnosis is based on clinical findings and further confirmatory tests, such as:

• MRI brain and spine: imaging modality of choice for both confirming and monitoring disease progression
• Evoked potentials: results not specific for MS but can be useful for the identification of subclinical lesions. Visual evoked potential testing can reveal slowing of conduction in the optic nerve due to demyelination
• Lumbar puncture: CSF evaluated for oligoclonal bands (OCB) and intrathecal IgG production. CSF protein levels can also be elevated. CSF OCB detection is not specific for MS and 5-10% patients diagnosed with MS do not show CSF abnormalities

Diagnosis of MS is made as per the McDonald diagnostic criteria, comprising clinical, radiographic, and laboratory factors. MS can be diagnosed when a patient has experienced at least two clinical attacks, or has evidence of MS plaques in at least two distinct brain areas on an MRI. This is described as having plaques separated in time and space.

Image Source: doi.org (2022), s00062-022-01144-3, Licensed under a creative commons licence. Available for free at: https://doi.org/10.1007/s00062-022-01144-3 (Accessed: 17 July 2024)

Classification of MS

• Relapsing remitting MS (RRMS): approximately 85% of cases. Characterised by unpredictable relapses followed by periods of remission, which can last for months to years. Deficits caused by relapses may resolve or be permanent. If they resolve completely between attacks it is classified as benign MS.
• Primary progressive MS (PPMS): approximately 10% of cases. Patients do not recover from their first relapse, and symptoms decline continuously without clear attacks or episodes of remission. This subtype is common in patients with older disease onset.
• Secondary progressive MS (SPMS): seen in approximately 80% of patients who initially present with RRMS. Characterised by  progressive neurological decline between acute attacks without definite periods of remission. SPMS causes the highest amount of disability.
• Progressive relapsing MS (PRMS): characterised by progressive worsening of neurological symptoms with superimposed flares from the onset of MS.
• Clinically isolated syndrome (CIS): a single episode of neurological symptoms lasting over 24 hours. Individuals who develop CIS may or may not go on to develop MS. Further investigation with an MRI is recommended. The detection of oligoclonal bands in CSF is the most sensitive predictor of conversion from CIS to MS.

Management of multiple sclerosis

Treatment of MS has two main aspects: treatment of acute flares and treatment of the underlying condition with disease-modifying agents. Disease-modifying treatments are not routinely administered during an acute flare.

Treatment of acute relapse

1. Methylprednisolone: accelerates recovery from an acute attack of MS; it does not alter the disease course. Systematic reviews have shown the efficacy of corticosteroids in reducing symptoms of an acute relapse however the optimal dose, route of administration and duration of treatment remain unclear.
2. Plasma exchange: used short term during acute attacks if steroids are ineffective or are contraindicated.

Disease-modifying treatment

1. Interferons (IFN), e.g. IFN beta, peginterferon
2. Monoclonal antibodies, e.g. natalizumab, alemtuzumab, ocrelizumab
3. Sphingosine-1-phosphate (S1P)-receptor modulators, e.g. Fingolimod, Siponimod
4. Cyclophosphamide can be used for the treatment of aggressive MS

Note that natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), a rare and often fatal condition caused by the JC virus.

The Expanded Disability Status Scale (EDSS) is a scale used for quantifying disability in patients with multiple sclerosis and monitoring the changes in the level of their disability over time. It takes into account how ambulant patients are, and the severity of pyramidal, brainstem and cerebellar symptoms. In addition to this, bowel, bladder and visual symptoms are ranked. It has been widely used in clinical trials and in assessing people with MS.

Neuroinflammatory disorders

Neuromyelitis optica spectrum disorder

Previously known as Devic disease, neuromyelitis optica (spectrum disorder) (NMO)(SD) presents with recurrent episodes of unilateral or bilateral optic neuritis associated with myelopathy.

It is caused by an immune-mediated attack on aquaporin 4 (AQP4), which is a neural channel protein. NMO-IgG antibody selectively binds AQP4 causing demyelination and axonal death.

Symptoms caused by optic neuritis include:

• Loss or blurring of vision; NMOSD often affects both eyes, unlike MS
• Eye pain with movement
• Loss of colour vision

Symptoms caused by transverse myelitis include:

• Loss of bowel or bladder control or urinary retention
• Spasticity (increased muscle tone or stiffness in the arms or legs)
• Weakness, numbness, or loss of sensation

Blood testing for the AQP4 antibody is highly specific (>99%) and its sensitivity ranges from 48-87%.

Treatments consist of IV corticosteroids and plasma exchange. Immunosuppressive drugs such as mycophenolate mofetil, rituximab, and azathioprine have also been found to be beneficial in treatment. MS treatment is often ineffective in NMO.

Transverse myelitis

This describes inflammation of both sides of a section of the spinal cord due to damage to the myelin sheath.

Symptoms include:

• Pain
• Sensory loss in upper and lower limbs
• Motor weakness in upper and lower limbs
• Bladder and bowel dysfunction

Various conditions can cause transverse myelitis:

• Immune disorders such as MS, NMO, and post-infectious or post-vaccine autoimmune phenomena.
  Myelin oligodendrocyte glycoprotein (MOG) antibody associated disease (MOGAD) causing autoimmune demyelination of the CNS, in particular the optic nerves, brain and spinal cord, can also cause transverse myelitis. Anti-MOG antibodies are present in cases of MOGAD
• Viral infections, including herpes simplex, varicella zoster, cytomegalovirus, Epstein-Barr virus, hepatitis B, mumps, measles, and rubella
• Bacterial infections such as syphilis, TB, actinomyces, pertussis, tetanus, diphtheria, and Lyme disease
• Fungal infections including aspergillus
• Parasites, including toxoplasmosis, cysticercosis, and schistosomiasis
• Inflammatory disorders, such as sarcoidosis, systemic lupus erythematosus, Sjögren’s syndrome, mixed connective tissue disease, scleroderma, and Beçhet’s syndrome

Image Source: Wikimedia Commons (2010). Transverse_myelitis_MRI, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Transverse_myelitis_MRI.jpg (Accessed: 17 July 2024)

Transverse myelitis is diagnosed by MRI of the spinal cord, which confirms the presence of a lesion. An MRI brain may provide clues to underlying causes, especially MS.

Blood tests may be performed to rule out differentials and identify the cause of transverse myelitis, including the presence of autoantibodies (anti-AQP4, anti-myelin oligodendrocyte) and paraneoplastic antibodies. CSF analysis often shows elevated protein and leukocytes.

Management depends on the cause.

Autoimmune encephalitis

Autoimmune encephalitis comprises a group of non-infectious immune-mediated inflammatory disorders of the brain involving the cortical deep grey matter, with or without involvement of white matter, meninges, or spinal cord.

• Common causes of autoimmune encephalitis include acute disseminated encephalomyelitis (ADEM) and anti-NMDA (N-methyl-D-aspartate) receptor encephalitis.
• Paraneoplastic encephalitis is seen most with small cell lung, breast, ovarian and testicular cancer, and Hodgkin’s lymphoma. Antineoplastic antibodies (Anti-Hu, Yo, Ri and Ma) are often positive.
• MRI may often be normal in autoimmune encephalitis therefore, diagnosis is made by CSF analysis including analysis for CSF antibodies.

References

• Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005 Dec;58(6):840-6
• Brooks BR, Miller RG, Swash M, et al; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1:293-299
• Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278-86
• Wingerchuk DM, Lucchinetti CF. Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis. Curr Opin Neurol. 2007 Jun;20(3):343-50
• Compston A, Coles A. Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17
• West TW, Hess C, Cree BA. Acute transverse myelitis: demyelinating, inflammatory, and infectious myelopathies. Semin Neurol. 2012 Apr;32(2):97-113
• Graus  F , Titulaer  MJ , Balu  R , et al . A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol2016;15:391–404