MS is more common in people who live farther from the equator, although exceptions exist. These exceptions include ethnic groups that are at low risk far from the equator such as the Samis, Amerindians, Canadian Hutterites, New Zealand Māori, and Canada's Inuit, as well as groups that have a relatively high risk close to the equator such as Sardinians, inland Sicilians, Palestinians and Parsis. The cause of this geographical pattern is not clear. While the north-south gradient of incidence is decreasing, as of 2010 it is still present.

MS is more common in regions with northern European populations and the geographic variation may simply reflect the global distribution of these high-risk populations. Decreased sunlight exposure resulting in decreased vitamin D production has also been put forward as an explanation. A relationship between season of birth and MS lends support to this idea, with fewer people born in the northern hemisphere in November as compared to May being affected later in life. Environmental factors may play a role during childhood, with several studies finding that people who move to a different region of the world before the age of 15 acquire the new region's risk to MS. If migration takes place after age 15, however, the person retains the risk of their home country. There is some evidence that the effect of moving may still apply to people older than 15.

The cause of MS is unknown; however, it is believed to occur as a result of some combination of genetic and environmental factors such as infectious agents. Theories try to combine the data into likely explanations, but none has proved definitive. While there are a number of environmental risk factors and although some are partly modifiable, further research is needed to determine whether their elimination can prevent MS.

Socioeconomic correlates of health have been well established in the study of heart disease, lung cancer, and diabetes. Many of the explanations for the increased incidence of these conditions in people with lower socioeconomic status (SES) suggest they are the result of poor diet, low levels of exercise, dangerous jobs (exposure to toxins etc.) and increased levels of smoking and alcohol intake in socially deprived populations. Hesdorffer et al. found that low SES, indexed by poor education and lack of home ownership, was a risk factor for epilepsy in adults, but not in children in a population study. Low socioeconomic status may have a cumulative effect for the risk of developing epilepsy over a lifetime.

Approximately 2 million people in the world suffer from multiple sclerosis Tumefactive multiple sclerosis cases make up 1 to 2 of every 1000 multiple sclerosis cases. This means that only around 2000 people in the world suffer of tumefactive MS. Of those cases, there is a higher percentage of females affected than males. The median age of onset is 37 years.

As in general MS, there are differences for gender, ethnicity and geographic location. Based on epidemiological studies, there are about 3 times more female MS patients than male patients, indicating a possibility of an increased risk due to hormones. Among different ethnic groups, MS is the most common among Caucasians and seems to have a greater incidence at latitudes above 40° as compared to at the equator. While these associations have been made, it is still unclear how they result in an increased risk of MS onset.

There were also observations that hippocampal sclerosis was associated with vascular risk factors. Hippocampal sclerosis cases were more likely than Alzheimer's disease to have had a history of stroke (56% vs. 25%) or hypertension (56% vs. 40%), evidence of small vessel disease (25% vs. 6%), but less likely to have had diabetes mellitus (0% vs. 22%).

Originally found in neuromyelitis optica, this autoantibody has been associated with other conditions. Its current spectrum is as following:

- Seropositive Devic's disease, according to the diagnostic criteria described above

- Limited forms of Devic's disease, such as single or recurrent events of longitudinally extensive myelitis, and bilateral simultaneous or recurrent optic neuritis

- Asian optic-spinal MS - this variant can present brain lesions like MS.

- Longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease

- Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem

- Some cases of tumefactive multiple sclerosis

Though for the most of the cases these diseases are still idiopathic, recent researchs have found the causes for some of them, making them not idiopathic anymore. There are currently two identified auto-antibodies and a genetic variant. The autoantibodies are anti-AQP4 and anti-MOG so far and the genetic variant is a mutation in the gene NR1H3.

The prognosis of this disease is very variable and can take three different courses: a monophasic, not remitting;

remitting;

and finally, progressive, with increase in deficits.

Diffuse myelinoclastic sclerosis, sometimes referred to as Schilder's disease, is a very infrequent neurodegenerative disease that presents clinically as pseudotumoural demyelinating lesions, that make its diagnosis difficult. It usually begins in childhood, affecting children between 5 and 14 years old, but cases in adults are possible.

This disease is considered one of the borderline forms of multiple sclerosis because some authors consider them different diseases and others MS variants. Other diseases in this group are neuromyelitis optica (NMO), Balo concentric sclerosis and Marburg multiple sclerosis.

Incidence of demyelinating diseases vary from disorder to disorder. Some conditions, such as Tabes dorsalis appear predominantly in males and begins in mid-life. Optic neuritis on the other hand, occurs preferentially in females typically between the ages of 30 and 35. Other conditions such as multiple sclerosis vary in prevalence depending on the country and population. This condition can appear in children as well as adults.

Balo lesions have been reported alone, but also associated to standard multiple sclerosis, neuromyelitis optica, CADASIL and progressive multifocal leukoencephalopathy

A clinically isolated syndrome (CIS) is a clinical situation of an individual's first neurological episode, caused by inflammation or demyelination of nerve tissue. An episode may be monofocal, in which symptoms present at a single site in the central nervous system, or multifocal, in which multiple sites exhibit symptoms. CIS with enough paraclinical evidence can be considered as a clinical stage of Multiple Sclerosis (MS). It can also be retrospectively diagnosed as a kind of MS when more evidence is available.

Brain lesions associated with a clinically isolated syndrome may be indicative of several neurological diseases, like multiple sclerosis (MS) or Neuromyelitis optica. In order for such a diagnosis, multiple sites in the central nervous system must present lesions, typically over multiple episodes, and for which no other diagnosis is likely. A clinically definitive diagnosis of MS is made once an MRI detects lesions in the brain, consistent with those typical of MS. Other diagnostics include cerebrospinal fluid analysis and evoked response testing.

Currently it is considered that the best predictor of future development of clinical multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging during the CIS. It is normal to evaluate diagnostic criteria against the "time to conversion to definite".

In 2001, the International Panel on the Diagnosis of Multiple Sclerosis issued the McDonald criteria, a revision of the previous diagnostic procedures to detect MS, known as the Poser criteria. "While maintaining the basic requirements of dissemination in time and space, the McDonald criteria provided specific guidelines for using findings on MRI and cerebrospinal fluid analysis to provide evidence of the second attack in those individuals who have had a single demyelinating episode and thereby confirm the diagnosis more quickly." Further revisions were issued in 2005.

The pathology of the tumefactive demyelinating lesion (TDL) is heterogeneous. In acute phase, the plaques of lesions were characterized by massive demyelination with relatively axonal preservation associated with reactive astrocytosis and infiltration of macrophages. In plaques of chronic lesions, demyelinated lesions with relative axonal preservation and sharply defined margins were major findings. And myelin-laden macrophages accumulate at the edges of plaques and stay inactive

There are several conditions can produce tumefactive lesions. This is known because in some special cases the etiology can be identified. For example, there are some cases of NMO, misidentified as MS and treated with interferon-beta by mistake. Some of these patients developed tumefactive lesions. Anyway, it is important to have into account that NMO itself can also produce them

Some other cases have been found related to viral infection, some others related to NMOSD, others could be paraneoplastic. Also some cases could be related to hormonal treatments

Other possible cause are immunomodulatory combinations. In particular, it has been found that switching from standard MS therapies to fingolimod can trigger tumefactive lesions in some MS patients

While standard multiple sclerosis process has an autoimmune response after the breach of the blood-brain barrier, in tumefactive MS things do not process in the same way, and demyelinating lesions do not always show antibody damage. Subjects with tumefactive multiple sclerosis display elevated levels of choline (Cho)/creatine ratio and increased lactate which is associated with demylinating diseases. Cases also display oligoclonal bands in the cerebrospinal fluid.

The disease is heterogeneous and the lesions do not always comply with the requirements for multiple sclerosis diagnosis (dissemination in time and space). In these cases it is only possible to speak about tumefactive demyelination (TD).

In general, it is accepted that the two main causes of pseudo-tumoral lesions are Marburg multiple sclerosis and acute disseminated encephalomyelitis (ADEM). Tumefactive demyelination of the spinal cord is rare but it has been reported

Damage is not confined to the demyelinating area. Wallerian degeneration outside the lesions has been reported.

Prognosis depends on the condition itself. Some conditions such as multiple sclerosis depend on the subtype of the disease and various attributes of the patient such as age, sex, initial symptoms and the degree of disability the patient experiences. Life expectancy in Multiple sclerosis patients is 5 to 10 years lower than unaffected people. MS is an inflammatory demyelinating disease of the

central nervous system (CNS) that develops in genetically susceptible individuals after exposure to unknown environmental trigger(s). The bases for MS are unknown but are strongly suspected to involve immune reactions against autoantigens, particularly myelin proteins. The most accepted hypothesis is that dialogue between T-cell receptors and myelin antigens leads to an immune attack on the myelin-oligodendrocyte complex. These interactions between active T cells and myelin antigens provoke a massive destructive inflammatory response and promotes continuing proliferation of T and B cells and macrophage activation, which sustains secretion of inflammatory mediators. Other conditions such as central pontine myelinolysis have about a third of patients recover and the other two thirds experience varying degrees of disability. There are cases, such as transverse myelitis where the patient can begin recovery as early as 2 to 12 weeks after the onset of the condition.

Balo concentric sclerosis in children has been reported to behave different from adults

Marburg acute multiple sclerosis, also known as Marburg multiple sclerosis or acute fulminant multiple sclerosis, is considered one of the multiple sclerosis borderline diseases, which is a collection of diseases classified by some as MS variants and by others as different diseases. Other diseases in this group are neuromyelitis optica (NMO), Balo concentric sclerosis, and Schilder's disease. The graver course is one form of malignant multiple sclerosis, with patients reaching a significant level of disability in less than five years from their first symptoms, often in a matter of months.

Sometimes Marburg MS is considered a synonym for tumefactive MS, but not for all authors.

Natalizumab (Tysabri) was approved in 2004 by the FDA for multiple sclerosis (MS). It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of PML. All 3 initial cases were taking natalizumab in combination with interferon beta-1a. After a safety review the drug was returned to the market in 2006 as a monotherapy for MS under a special prescription program. As of May 2011, over 130 cases of PML had been reported in MS patients, all in patients who had taken natalizumab for more than a year. While none of them had taken the drug in combination with other disease-modifying treatments, previous use of MS treatments increases the risk of PML between 3 and 4-fold. The estimated prevalence of PML in MS is 1.5 cases per thousand natalizumab users. Around 20% of MS patients with PML die, and most of the rest are very disabled.

A person with MS developed PML and died during a 4-year course of dimethyl-fumarate.

PML is most common in people with HIV1 infection; prior to the advent of effective antiretroviral therapy, as many as 5% of people with AIDS eventually developed PML. It is unclear why PML occurs more frequently in AIDS than in other immunosuppressive conditions; some research suggests the effects of HIV on brain tissue, or on JCV itself, make JCV more likely to become active in the brain and increase its damaging inflammatory effects.

PML can occur in people on chronic immunosuppressive therapy like corticosteroids, for organ transplant, in people with cancer (such as Hodgkin’s disease, leukemia, or lymphoma) and individuals with autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, sarcoidosis, and systemic lupus erythematosus with or without biological therapies that depress the immune response and allow JC virus reactivation. These therapies include efalizumab, belatacept, rituximab, natalizumab, infliximab, cytotoxic chemotherapy, corticosteroids, and various transplant drugs such as tacrolimus.

Marburg variant of MS is an acute fulminant demyelinating process which in most cases progresses inexorably to death within 1–2 years. However, there are some reports of Marburg MS reaching stability by three years.

Researchers do not fully understand what causes PLS, although it is thought it could be due to a combination of environmental and genetic factors. Studies are being done to evaluate the possible causes, although linking causality can be difficult due to the relatively low number of people who are diagnosed with PLS.

Juvenile PLS may be caused by the ALS2 gene, although this condition is very rare.

A hereditary CNS demyelinating disease is a demyelinating central nervous system disease that is primarily due to an inherited genetic condition. (This is in contrast to autoimmune demyelinating conditions, such as multiple sclerosis, or conditions such as central pontine myelinolysis that are associated with acute acquired insult.)

Examples include:

- Alexander disease

- Canavan disease

- Krabbe disease

- leukoencephalopathy with vanishing white matter

- megalencephalic leukoencephalopathy with subcortical cysts

- metachromatic leukodystrophy

- X-linked adrenoleukodystrophy

The importance of correctly recognizing progressive muscular atrophy as opposed to ALS is important for several reasons.

- 1) the prognosis is a little better. A recent study found the 5-year survival rate in PMA to be 33% (vs 20% in ALS) and the 10-year survival rate to be 12% (vs 6% in ALS).

- 2) Patients with PMA do not suffer from the cognitive change identified in certain groups of patients with MND.

- 3) Because PMA patients do not have UMN signs, they usually do not meet the "World Federation of Neurology El Escorial Research Criteria" for “Definite” or “Probable” ALS and so are ineligible to participate in the majority of clinical research trials such as drugs trials or brain scans.

- 4) Because of its rarity (even compared to ALS) and confusion about the condition, some insurance policies or local healthcare policies may not recognize PMA as being the life-changing illness that it is. In cases where being classified as being PMA rather than ALS is likely to restrict access to services, it may be preferable to be diagnosed as "slowly progressive ALS" or "lower motor neuron predominant" ALS.

An initial diagnosis of PMA could turn out to be slowly progressive ALS many years later, sometimes even decades after the initial diagnosis. The occurrence of upper motor neurone symptoms such as brisk reflexes, spasticity, or a Babinski sign would indicate a progression to ALS; the correct diagnosis is also occasionally made on autopsy.

Juvenile primary lateral sclerosis (JPLS) ", also known as primary lateral sclerois (PLSJ)," is a rare genetic disorder, with a small number of reported cases, characterized by progressive weakness and stiffness of muscles in the arms, legs, and face. The disorder damages motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement.

Juvenile Primary Lateral Sclerosis is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, parents of affected individuals each carry one copy of the altered gene, but do not show any signs or symptoms.

Mutations in the ALS2 gene, found on Chromosome 2, are responsible for causing Juvenile Primary Lateral Sclerosis. The ALS2 gene provides instructions for making a protein called alsin. Alsin is abundant in motor neurons, but its function is not fully understood. Mutations in the ALS2 gene in this disorder disrupt the instructions for producing alsin. As a result, alsin is unstable and decays rapidly, or it is disabled and cannot function properly. It is currently unknown how the loss of functional alsin protein causes the death of motor neurons and the symptoms of juvenile primary lateral sclerosis.

The cause of PBP is unknown. One form of PBP is found to occur within patients that have a CuZn-superoxide dismutase (SOD1) mutation. Progressive bulbar palsy patients that have this mutation are classified with FALS patients, Familial ALS (FALS) accounts for about 5%-10% of all ALS cases and is caused by genetic factors. Within these, about 20-25% are linked to the SOD1 mutation. It is not currently known if and how the decreased SOD1 activity contributes to Progressive Bulbar Palsy or FALS, and studies are being done in patients and transgenic mice to help further understand the impact of this gene on the disease.

A case study was done on a 42-year-old woman who complained of muscle weakness 10 months prior to admission in the hospital. Upon neurological examination, the patient showed muscle atrophy, fasciculation in all limbs and decreased deep tendon reflexes. The patient’s older brother, father, and paternal uncle had previously all died of ALS or an ALS type syndrome. The patient developed Progressive Bulbar Palsy, became dependent on a respirator, and had two episodes of cardiac arrest. The patient died from pneumonia two years after the onset of the disease. After studying the patient, it was found that the patient had a two base pair deletion in the 126th codon in exon 5 of the SOD1 gene. This mutation produced a frameshift mutation, which led to a stop codon at position 131. SOD1 activity was decreased by about 30%. The patient’s histological examination showed severe reduction in lower motor neurons. Upon further study, this case proved to be important because it demonstrated that SOD1 mutations might not effect steady neuropathological changes, and that environmental and genetic factors might affect the phenotype of the SOD1 mutations.