27th June 2023

Demyelinating diseases

Demyelinating diseases of the central nervous system

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune inflammatory condition leading to the development of plaques of demyelination within the central nervous system (CNS). Over 2 million adults worldwide are known to have MS, with much higher incidences being reported in wealthy countries and those located at the extremities of the poles. The mean age of diagnosis is 32 years, and women are up to four times as likely to develop the condition as men.

Presentation & Diagnosis

Most patients with MS will experience a relapsing-remitting form of the disease, describing a full recovery from their symptoms over the course of a few weeks after their appearance. After some time, their disease may take on a secondary progressive form, with a gradually reducing clinical recovery from symptoms due to increasing levels of permanent axonal damage. Those who present with a primary progressive form of MS will have experienced this accumulation of neurological deficits from the onset of diagnosis.

Rarely, some patients may experience only a single episode of one of these syndromes, in association with a single plaque of demyelination which never recurs – these cases are referred to as a ‘clinically isolated syndrome’. Occasionally, a single asymptomatic plaque of demyelination can be incidentally identified on imaging – these cases are referred to as ‘radiographically isolated syndromes’. Both diagnoses can remain isolated or be confirmed as manifestations of MS if the patient develops additional signs or findings suggestive of MS in the future.

Most cases of MS present as a young adult describing an experience of one or more clinically isolated neurological syndromes. These are the clinical manifestations of acute plaques of demyelination appearing and resolving, which will cause varying syndromes depending on the location of the inflammation. These symptoms progressively develop over the course of hours to days and can also accumulate if multiple lesions are present.

Common syndromes include the following:

• Optic neuritis – causing monocular visual blurring or scotoma, which can be painful or painless
• Internuclear ophthalmoplegia – causing diplopia and can be associated with a relative afferent pupillary defect on examination
• Cerebellar syndrome – causing ataxia and/or vertigo
• Brainstem syndrome – causing dysarthria or dysphagia
• Partial transverse myelitis – causing paraesthesia, numbness, limb weakness, urinary incontinence, erectile dysfunction

According to the McDonald criteria, a diagnosis of MS can only be made when there is evidence of demyelination both disseminated in time and space. This can be determined by combining a detailed clinical history and magnetic-resonance imaging (MRI) of the CNS to confirm the inflammatory origin of the symptoms. MRI of the head may assist the diagnosis by revealing asymptomatic plaques of demyelination. Plaques of active demyelination are most visible on T2-weighted MRI sequences, where they will appear as hyperintense ovoid lesions within the white matter. Older plaques of persisting axonal damage can also be seen on MRI. Periventricular lesions can often be seen as if ‘radiating’ from the corpus callosum, a sign known as ‘Dawson’s fingers’. On a cellular level, these plaques reflect areas of localised but reversible loss of oligodendrocytes with astroglial scarring. Over time, these changes can lead to axonal injury, a form of neuronal damage leading to often permanent neurological symptoms.

Although further investigations are not usually required, other markers can be used to increase diagnostic confidence of a diagnosis of MS. The presence of oligoclonal bands in cerebrospinal fluid collected through a lumbar puncture is a recognised form of evidence for dissemination of the demyelination in time. If a patient presents with atypical features, antibody testing can be performed for Aquaporin-4 (a specific biomarker for neuromyelitis optica spectrum disorder) and myelin oligodendrocyte glycoprotein IgG autoantibody (a biomarker for MOG antibody-associated disease).

Management

High-dose oral or intravenous steroids are prescribed for acute flare of demyelination, for a duration of three to seven days. Disease-modifying therapies are used in the relapsing-remitting form of MS to reduce the frequency and severity of relapses. There are more than a dozen available on the NHS, and they are usually divided according to their method of administration:

• Dimethyl fumarate – oral medication whose mechanism of action is believed to involve the activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.
• Oral Teriflunomide – works by inhibiting pyrimidine biosynthesis and disrupting the interaction of T cells with antigen presenting cells
• Oral sphingosine 1-phosphate receptor (S1PR) modulators, e.g. Fingolimod
• Subcutaneous injections of monoclonal antibodies, e.g. Natalizumab (anti-integrin), Ocrelizumab (anti-CD20), Rituximab (anti-CD20), Ofatumumab (anti-CD20) and Alemtuzumab (anti-CD52).
• Older injectable therapies, e.g. recombinant human interferon beta-1b and beta-1a and Glatiramer acetate

Neuromyelitis Optica Spectrum Disorder

Neuromyelitis Optica Spectrum Disorders (NMOSD) represent a group of inflammatory conditions of the central nervous system characterised by florid demyelination within the optic nerves and spinal cord. Neuromyelitis Optica itself presents with a stepwise deterioration in the context of recurrent attacks of optic neuritis (often bilateral) and transverse myelitis, which can be longitudinally extensive. The diagnosis of NMOSD can be confirmed through the presence of Aquaporin-4 antibodies in the serum, the titres of which correlate closely with disease severity and activity. Acute flares are aggressively treated with high-dose intravenous steroids for three to five days. Multiple disease-modifying therapies are available for NMOSD, including Eculizumab (monoclonal antibody targeting C5) and Inebilizumab (monoclonal antibody targeting CD19).

Myelin-Oligodendrocyte-Glycoprotein Antibody-associated Disease

Myelin-Oligodendrocyte-Glycoprotein antibody associated disease (MOGAD) is another immune-mediated inflammatory disorder characterised by acute attacks of demyelination within the central nervous system. Like multiple sclerosis and NMOSD, this condition can be either relapsing-remitting or monophasic, although it primarily affects children rather than young adults. Clinical manifestations include the development of optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis (ADEM). ADEM presents with encephalopathy and multifocal neurological symptoms or signs. Anti-MOG immunoglobulin G (MOG-IgG) and MRI of the brain and spine are key to the diagnosis of MOGAD. High-dose intravenous steroids can be used for up to five days when an acute attack is diagnosed; however, there is limited scope for disease-modifying therapies as most patients present with a monophasic disease.

Demyelinating diseases of the peripheral nervous system

Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) describes a collection of acute immune-mediated polyneuropathies usually triggered by a recent upper respiratory infection or gastroenteritis (especially in association with infection by Campylobacter jejuni). Vaccination within the previous 4 weeks also appears to be a common trigger. Typical clinical features include a symmetrical muscle weakness which gradually appears over the course of days to short weeks. On examination, flaccid weakness of the upper and lower limbs is easily identified, starting in the lower limbs and following a distal-to-proximal progression. Absent or greatly reduced deep tendon reflexes are also a frequent finding. Cranial nerve involvement, such as facial nerve palsies, oropharyngeal weakness and ophthalmoplegia, can also be seen. Autonomic symptoms such as arrhythmias, hypotension and respiratory muscle weakness are common complications which may require review by the critical care team and warrant close monitoring, such as regular forced vital capacity testing. The diagnosis of GBS is usually made clinically, however, it can be assisted by using nerve conduction studies or a lumbar puncture, which reveals high protein levels within the cerebrospinal fluid.

The most common form of the disease, acute inflammatory demyelinating polyneuropathy (AIDP), is associated with clinical and electrophysiological evidence of peripheral demyelination and lymphocytic infiltration of the sural nerve in biopsies. In these cases, a focal inflammatory response affecting the myelin sheath or myelin-producing Schwann cells causes the development of areas of demyelination along the peripheral nerves. This phenomenon leads to a slowing of the propagation of saltatory electrical signalling, which manifests as muscle weakness when a threshold is reached. Axonal loss is a phenomenon that can be observed in most forms of GBS but can also be a predominant feature in certain variants. The Miller-Fisher variant of GBS is characterised by the clinical triad of ataxia, ophthalmoplegia and areflexia, in association with the presence of antibodies against GQ1b.

Pharmacological treatment of GBS includes intravenous immunoglobulins for five days to patients within four weeks of symptom onset, or plasma exchange therapy as an alternative. Regular assessment of respiratory muscle function with forced vital capacity is important to identify early involvement of the respiratory muscles; respiratory deterioration often warrants admission to intensive care for consideration of intubation and ventilation.

Chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a subset of rare, immune-mediated polyradiculoneuropathies. Although multiple forms exist, CIDP typically presents with a slowly progressive symmetrical motor neuropathy affecting both proximal and distal peripheral nerves. Sensory impairment may also be identified, although usually less severe than the limb weakness. Examination findings include areflexia with signs of lower motor neuron disease and patchy sensory loss. High protein levels are found on cerebrospinal fluid analysis. Nerve conduction studies are key to diagnosis and will reveal multiple partial conduction blocks and prolonged distal motor latency, suggestive of demyelination. The presence of ‘onion bulb formations’ of axons are a pathognomonic finding frequently seen in biopsy results. CIDP can be treated with intravenous immunoglobulins or plasma exchange, although intravenous high-dose steroids are an alternative.

Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is a spectrum of primary hereditary disorders causing both motor and sensory neuropathies which are slowly progressive. CMT are typically inherited in an autosomal dominant manner, although recessive and X-linked forms have been identified as well. There are a wide number of mutations known to cause CMT.

The most common form of CMT is CMT1a, which is associated with a duplication of the PMP22 gene leading to cumulative damage to the myelin sheath of the peripheral nerve axons. Patients with CMT1 will often present as teenagers or young adults with distal weakness and paraesthesia, causing frequent falls and ankle sprains. On examination, a gradual loss of proprioception and vibration can be identified. Over time, the atrophy will often lead to foot deformities such as pes cavus and hammer toes. Sleep apnoea is also commonly seen in these patients.

Patients with CMT2 commonly present in the second or third decade of life with distal symptoms such as reduced sensation and muscle weakness with atrophy. This form of the condition is typically associated with direct damage to the axons. Mutations to the MFN2 gene are associated with CMT2a, which is the most common cause of CMT2.

Electromyography with subsequent genetic testing is key to establishing a reliable diagnosis for most patients. Management remains supportive, with daily physiotherapy exercises and orthotics playing a central role in reducing the severity of deformities. Disability is known to increase with age, although symptom severity, age of onset and rate of progression vary considerably. Patients with CMT are also considered to be at higher risk from iatrogenic neurotoxicity, therefore, the disease is listed as a contra-indication to several drugs such as amiodarone, vincristine and tacrolimus.