Differential diagnosis includes:

  • Migraine
  • Cerebral neoplasms (primary and secondary)
  • Nutritional deficiencies (eg. B12 or copper)
  • Compressive lesions of the spinal cord
  • Infections (eg. syphilis, HIV)
  • Amyotrophic lateral sclerosis
  • Steroid sensitive relapsing disorders (eg. systemic lupus erythematosus, neurosarcoidosis)
  • Recurrent infarcts
  • Paraneoplastic syndromes
  • Psychiatric disease/functional symptoms.
  • Multiple Sclerosis

It is Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS) lesions that can lead to severe physical or cognitive disability as well as neurological defects. Although the etiology and pathogenesis of MS remains unclear, the cause of MS is multifactorial and include genetic predisposition together with environmental factors such as exposure to infectious agents, vitamin deficiencies, and smoking. These agents are able to trigger a cascade of events in the immune system which lead to neuronal cell death accompanied by nerve demyelination and neuronal dysfunction.

The disease is diagnosed on the basis of clinical findings and supporting evidence from ancillary tests, such as magnetic resonance imaging (MRI) of the brain and examination of the cerebrospinal fluid (CSF). MS typically presents in adults 20 to 45 years of age; occasionally, it presents in childhood or late middle age.

 

Neurologists agree that patients may be grouped into four major categories based on the course of disease:

  1. Relapsing–remitting MS:the most common form, affecting about 85% of MS patients. It is marked by flare-ups (relapses or exacerbations) of symptoms followed by periods of remission, when symptoms improve or disappear.
  2. Secondary progressive MS:may develop in some patients with relapsing–remitting disease. For many patients, treatment with disease-modifying agents helps delay such progression. The disease course continues to worsen with or without periods of remission or leveling off of symptom severity (plateaus).
  3. Primary progressive MS:affects approximately 10% of MS patients. Symptoms continue to worsen gradually from the beginning. There are no relapses or remissions, but there may be occasional plateaus. This form of MS is more resistant to the drugs typically used to treat the disease.
  4. Progressive-relapsing MS:a rare form, affecting fewer than 5% of patients. It is progressive from the start, with intermittent flare-ups of worsening symptoms along the way. There are no periods of remission.

Pathogenesis

Inflammation of the white and gray matter tissues in the CNS due to focal immune cell infiltration and their cytokines are the incipient cause of damage in MS. Many studies have suggested T helper (Th) cell (also known as CD4+ T cells) intervention and adaptive immune responses which initiated by interaction between antigen presenting cells (APCs) with T lymphocytes play an important role in the initiation and progression of MS.

Pathogen-associated molecules simultaneously bind to toll-like receptors on APCs and production of specific cytokines that include interleukin (IL)-12, IL-23 and IL-4 begins that these cytokines induce CD4+ T cell differentiation intoTh1, Th2, or Th17 phenotypes which have ability to release special cytokines. Interferon gamma (IFNγ) or type II interferon and tumor necrosis factor alpha (TNF-α) are proinflammatory cytokines critical for innate and adaptive immunity.

These cytokines are produced by Th1 cells. They have the ability to promote inflammation by suppressing Th2 differentiation. Th2 cells secrete the anti-inflammatory cytokines, IL-4 and IL-13. IL-4 reduces pathological inflammation via increase in M2 macrophage (or repair macrophages) and alternative activation of M1 macrophages that promote inflammation. The effects of IL-13 on immune cells are similar to IL-4. This cytokine, by secretion of matrix metalloproteinase, has anti-inflammatory properties especially during allergic inflammation.  Th17 is another CD4+ T cells which induces a large number of cytokines (IL-17, IL-21, IL-22 and IL-26) which are capable of promoting inflammation.

B lymphocytes and their cytokines are other factors in the pathogenesis of MS. Lymphotoxin [or transforming growth factor beta (TGF-β)] and TNF-α produced by these cells promotes inflammation. In addition, these cells are capable of producing IL-10 which is an anti-inflammatory cytokine. Hence, B lymphocytes have both positive and negative effects in the development of MS.

Many studies have shown that in addition to the above-mentioned cells, CD8+ T cells (or cytotoxic T cells) can be found in MS lesions. These cells, via the production of cytolytic proteins such as perforin, mediate suppression and inactivation of CD4+ T cells. Moreover, these cells thorough increase vascular permeability, glial cells destroy and trigger of oligodendrocyte death play an important role in the pathogenesis of MS. In addition to CNS inflammation, the myelin repair process due to oligodendrocyte death is also impaired.

Fas ligand (FasL) is produced by lymphocyte cells. This ligand binds to Fas receptors [cell surface receptor that belongs to the TNF receptor superfamily] on oligodendrocyte cells which begins the apoptosis process of these cells. Therefore, the numbers of myelin synthesis cells reduce and will impair synthesis of the myelin sheath

Diagnosis

There is no single diagnostic test for MS. The diagnosis is based on evidence of   (1) at least two different lesions (plaques or scars) in the white matter of the CNS (the space dissemination criterion)

(2) at least two different episodes in the disease course (the time dissemination criterion)

(3) chronic inflammation of the CNS, as determined by analysis of the CSF (the inflammatory criterion).

The presence of one or more of these criteria allows a general diagnosis of MS, which may be refined according to the subsequent course of the disease. An international panel on the diagnosis of MS suggested that the time dissemination criterion should be confirmed by clinical signs on MRI at least 3 months after the previous clinical episode or on a previous MRI. The panel also suggested that the inflammatory criterion could replace the space dissemination criterion when the latter is missing at the clinical and paraclinical levels.

To make a diagnosis of MS, the physician must:

  • find evidence of damage in at least two separate areas of the CNS, which includes the brain, spinal cord, and optic nerves.
  • determine that the damaged areas developed at least 1 month apart.
  • exclude all other possible diagnoses.
  • observe that the symptoms last for more than 24 hours and occur as distinct episodes separated by 1 month or more.
  • perform an MRI (the most sensitive imaging test for MS)
  • perform a spinal tap and examination for oligoclonal bands.

At autopsy, multiple, discrete pink or gray areas that have a hard, rubbery texture are identified within the white matter. The lesions are composed of areas of myelin and oligodendrocyte loss along with infiltrates of inflammatory cells, including lymphocytes and macrophages. The relative preservation of axons and neurons within these lesions helps to differentiate MS from other destructive pathological processes that are accompanied by focal inflammation.

More than 30% of MS patients have moderate-to-severe spasticity, mostly in the legs. Initial clinical findings in MS patients are often sensory disturbances, the most common of which are paresthesias (numbness and tingling), dysesthesias (burning and “pins and needles”), diplopia, ataxia, vertigo, and bladder (urinary sphincter) disturbances. A common manifestation of MS is unilateral numbness affecting one leg that spreads to involve the other leg and rises to the pelvis, abdomen, or thorax. Sensory disturbances usually resolve but sometimes evolve into chronic neuropathic pain. Trigeminal neuralgia also occurs. Another common presenting sign of MS is optic neuritis, highlighted by complete or partial loss of vision.

Bladder dysfunction occurs in more than 90% of MS patients and results in weekly or more frequent episodes of incontinence in one-third of patients. At least 30% of patients experience constipation. Fatigue occurs in 90% of patients and is the most common work-related disability associated with MS. Sexual problems are often experienced as well.

Symptoms include:

  1. Pain on eye movement.
  2. Blurred vision.
  3. Upper and lower limb weakness.
  4. Unilateral or bilateral limb numbness and paresthesias.
  5. L’Hermitte’s phenomenon(short electric shock like sensation on neck movement.
  6. Blurred or double vision.
  7. Constipation, Urinary frequency, urge incontinence, erectile dysfunction.

Disease modifying treatment

First line treatments:

The interferon-ßs and glatiramer acetate have been used as first line DMTs for RRMS for over a decade.

Second line treatments:

Natalizumab has been demonstrated to reduce the rate of disability progression. Although these relative risk reduction figures appear greater than those seen with interferon-ß and glatiramer acetate, its use is limited due to the potentially devastating complication of progressive multifocal leukoencephalopathy due to a brain infection with JC virus.

Fingolimod (FTY720), the first oral treatment for RRMS, was listed on the PBS on 1 September 2011. This drug has a unique mode of action through the sphingosine 1-phosphate receptor which prevents lymphocyte trafficking through the lymph node and causes a reversible lymphopenia.

Other oral therapies currently undergoing preclinical trials include laquinimod, teriflunomide and BG12. The long term safety and exact role of these oral therapies in MS are yet to be established.

Third line and salvage therapeutic options:

In patients with aggressive disease who do not respond to treatment, other options include immunosuppression with cyclophosphamide or mitoxantrone, or high dose chemotherapy followed by autologous haematopoeitic stem cell transplant. The use of these strategies is limited by their lower tolerability and potentially serious adverse events.

Symptomatic treatment:

Troublesome symptoms may include spasticity, parasthesias, tremor, erectile dysfunction, depression and anxiety, fatigue and pain. Depression and anxiety are very common in MS, but psychoses are rare. Management options include counselling with a psychologist familiar with MS and antidepressants. Fatigue is common and may respond to amantidine 100 mg in the morning and at midday. Importantly, depression should always be considered as a cause in any MS patient complaining of fatigue. Pain is common and often under-recognised in MS and management includes counselling and medications (eg. amitriptyline, carbamazepine, gabapentin, pregabalin).