Multiple Sclerosis and Demyelinating Diseases

Multiple Sclerosis (MS) is an immune-mediated inflammatory disease that affects the myelinated axons in the central nervous system (CNS) and destroys the myelin and finally the axon in variable degree.

In the majority of cases the disease follows a pattern of relapses and remissions, with episodes of neurologic deficits that usually resolve completely or almost completely. In some cases though, there is a progressive neurologic decline from the onset of the disease.

Globally, approximately 2,000,000 people are affected by MS. The risk increases steadily from puberty till the age of 35 and then gradually decreases. MS is rarely diagnosed in children or in people older than 65 years.

The cause of MS remains unknown, but it is hypothesized that in results from a combination of genetic predisposition and a non-genetic trigger, such as an infection or low vitamin D levels. Environmental factors are also involved in the etiology of MS, as indicated by the geographical distribution concerning the incidence of MS.

The diagnosis of MS is based mostly in clinical findings and is supported by the findings of ancillary tests, especially the magnetic resonance imaging of the brain and spinal cord, the cerebrospinal fluid examination and neurophysiologic tests (evoked potentials). In order to put the diagnosis of MS, clinical and imaging criteria of disease dissemination in time and space must be fulfilled. 

Some of the most common symptoms of MS include visual disturbances (visual impairment, diplopia), muscular weakness, gait instability, sensory loss. In the basis of clinical criteria, MS course is classified in the following categories:

1. Relapsing Remitting MS (RRMS): It is characterized by attacks of neurologic symptoms that resolve and are followed by periods of remission without clinical symptoms. The patients with RRMS account for 85-90% of MS cases.
2. Clinically Isolated Syndrome (CIS): A single episode of neurologic symptoms, that is often the first clinical manifestation of MS. Indeed patients with CIS are at high risk of developing MS, although in some cases no further demyelinating activity is developed.
3. Secondary Progressive MS (SPMS): Patients with RRMS may convert to a pattern of progressive clinical deterioration over years, that may or may not include relapses.
4. Primary Progressive MS (PPMS): It accounts for 10-15% of MS patients, that present with a progressive neurologic decline from the onset of the disease, without relapses.

The therapeutic strategy of MS depends on the stage and the course of the disease. The treatment of the underlying immune disorder includes disease-modifying agents (such as interferons, monoclonal antibodies, glatiramer acetate, dimethyl fumarate, fingolimod) and immunosuppressive agents (such as mitoxanthrone, cyclophosphamide, azathioprine). Treatment of acute relapses includes mainly intravenous corticosteroids and in some cases plasma exchange or intravenous immunoglobulin. Finally, targeted pharmacologic and non-pharmacologic therapies are indicated for the management of MS symptoms such as spasticity, neuropathic pain, paroxysmal symptoms, sphincter disorders.

Acute multiple sclerosis is a rare fulminant variant of MS (Marburg variant). It manifests with acute or subacute neurologic symptoms and is characterized by large brain lesions with oedema which induce mass effect, resembling brain tumors. Brain biopsy is often needed in order to put the diagnosis. Because of the rarity of the disease, treatment is based in empirical facts and in bibliographic reports. In the acute phase high dose intravenous corticosteroids are administered, sometimes in combination with plasma exchange, followed by maintenance treatment with immunosuppressive and/or immunomodulatory agents.

Optic Neuritis (ON) is a demyelinating inflammation of the optic nerve. It may occur in the course of MS (it can be its first manifestation) or neuromyelitis optica, but it can also be an isolated clinical event. Occasionally ON is induced by an inflammatory process within the orbit or the paranasal sinuses, or occurs in the course of a systemic viral infection.

It is characterized by a rapid development of visual impairment (ranging from a small decrease in visual acuity to a complete loss of vision), usually in one eye, accompanied by dischromatopsia and ocular or retro-orbital pain which is often exacerbated by eye movement and may precede the visual loss. Symptoms may worsen by heat or exercise.

The gradual recovery with time is the rule in optic neuritis. Vision improves one week to several weeks after onset, even if untreated. Corticosteroids are used in the acute phase in order to speed up the recovery and relieve the pain.

Neuromyelitis Optica (NMO) or Devic’s disease is a rare demyelinating syndrome of the CNS, characterized by the simultaneous inflammation of the optic nerve and the spinal cord. It can be monophasic or recurrent.

NMO has clinical and imaging differences from MS (selective attack of the optic nerve and the spinal cord, presence of large lesions in the spinal cord extending over multiple vertebral segments, while white matter lesions in brain MRI and oligoclonal bands in CSF are uncommon). Often in the serum of patients autoantibodies against the protein aquaporin 4 are present, which are considered specific for NMO.

NMO can present in the course of a systemic autoimmune disease or be associated with certain infections.

Management of NMO clinical attacks is similar to MS relapses (IV corticosteroids or plasma exchange) but there is no established treatment for the prevention of the attacks. Immunosuppressive agents (azathioprine, mitoxanthrone, cyclophosphamide), monoclonal antibodies (rituximab) are usually administered, while other disease-modifying agents are still under trial.

Acute Disseminated Encephalomyelitis (ADEM) is a monophasic disease characterized by multifocal inflammation and demyelination in the CNS. It is common in children but extremely rare in adults and is usually associated to recent immunization or infectious illness.

ADEM should b prominent in the differential diagnosis of a demyelinating disease, especially versus MS, when there is a history of recent infection or immunization, a rapid development of symptoms (with involvement of the cerebral hemispheres, the brainstem, the cerebellum and the spinal cord), level of consciousness and mental status changes and seizures.

It is usually treated with high dose intravenous corticosteroids or if there is no response with plasma exchange.