Corticosteroids in neurology:


Dr. M.  R. Sivakumar,

Neuroimmunologist,  Apollo Hospitals,  Chennai , India.


Fifty years have lapsed since the corticosteroids (CS) were first employed as anti-inflammatory drugs in the Rheumatic diseases.(1) Initial optimism that these drugs would revolutionize the treatment of chronic inflammatory diseases like Rheumatoid arthritis turned to caution and thereafter to unease as the significant side effect profile of these agents became apparent. CS represents a classic therapeutic double - edged sword, with their profound anti-inflammatory activity balanced by serious risk of adverse effects in long-term, high-dose use.

Mechanism of action of corticosteroids:

CS exert their manifold effects on cells involved in immune and inflammatory responses primarily by modulating the transcription of a large number of genes. However they are also able to influence the translational and post-translational mechanisms by which proteins are synthesized , processed and exported from cells. As a steroid molecule, glucocorticoids are lipophilic and readily transported across the blood-brain barrier. They are readily absorbed from the gastrointestinal tract, and are effective in a wide range of doses that can be administered orally or parenterally. In fact there is much controversy regarding the optimum dose, route and the type of glucocorticoid that is most effective. It is also difficult to determine bio-equivalence between steroids. In spite of all these limitations, glucocorticoids remain the mainstay of treatment for all autoimmune disorders. Extensive research in molecular events of glucocorticoid function has been the subject of many reviews .

Virtually every cell has glucocorticoid receptors. These receptors are located on the cell membrane as well as in the cytosol. When glucocorticoid steroids enter the cell cytoplasm by binding to the membrane receptor, binding to the carboxyl terminal of the receptor results in a conformational change. The DNA binding domain on the receptor with the 2 zinc fingers become activated and the steroid-receptor complex attaches itself to the DNA after it travels to the nucleus. Such binding to DNA occur at specific nucleotide sequences, sites known as glucocorticoid responsive elements. These consensus sequences can be positive or negative depending on the ultimate effect on transcription at that promoter location. Accordingly, glucocorticoid treatment can result in enhanced or repressed transcription of specific molecules. Glucocorticoids have a wide array of activity and affect virtually every cell in the immune system. In particular, the cells of the lymphoid origin are affected. It is indeed an old observation that lymphopenia occur during glucocorticoid treatment. Function of T and B cells and macrophages are all affected, as also antigen presenting cells such as endothelial cells, microglia, and dendritic cells. These drugs can augment transcription, resulting in enhanced production of one lymphokine, while causing repression and down-regulation of the production of another.

Some of these activities are dose dependent and therefore these drugs tend to function differently at different doses. Glucocorticoids exert their beneficial effects at many levels. Virtually every cell type in the immune system is affected. Nevertheless, the macrophages appear to be most sensitive to corticosteroid effects, followed by B-cells, and then the T-lymphocytes. There are almost 3 times as many Glucocorticoid receptors on the macrophages as on B-cells and T-cells. Macrophages once considered as simple scavenging cells, are today recognized as primary pro-inflammatory cells, especially when antibodies and complement are involved in mediation of injury.

Macrophages home to sites of antibodies and activated complement and mediate injury. Corticosteroids down-regulate the expression of Fc and C3b receptors on macrophages and reduce the secretion of proinflammatory lymphokines and eicosanoids. Expression of class II histocompatibility molecules is reduced, which in turn inhibits antigen presentation. Expression of adhesion molecules is inhibited, which reduces cell-cell interactions. Endothelial cells no longer permit cell migration, and inhibition of metalloproteases further reduces breakdown of the blood-brain barrier .

Clinical use of Glucocorticoids:

There is no consensus among clinicians as to how corticosteroids are best used in clinical practice. In part, this is a reflection of the lack of studies to examine the optimal use of these agents. Most clinicians use oral or intravenous steroids as short or long-term treatments for a variety of immune mediated disorders.

Oral regimen:

Commonly used agents include prednisolone or dexamethasone. Prednisolone is usually used in doses of 1 mg/kg, and dexamethasone in doses of 4 to 16 mg per day. Oral regimens are suited for short or long-term use. During short-term use, steroids are given for a week or less and discontinued without a taper. For long-term use, prednisolone is the preferred drug since its short half-life will lend itself to the alternate day regimen. They stabilize the blood brain barrier, and affect mostly macrophage and some B-cell function with limited effects on the T-cells.

What are the advantages and disadvantages of these agents?
Dexamethasone is more anti-phlogistic, less mineralocorticoid than prednisone, and therefore a better choice. However, the long acting nature of the compound (half-life of 36 to 72 hours) does not lend itself to alternate-day regimen (see below).

What is the bio-equivalence of prednisolone and dexamethasone?
The approximate bio-equivalence is determined by a combination of relative equivalence and the biological half-life. For example, the relative equivalence of dexamethasone to prednisolone is 5, since dexamethasone is 25 fold more potent than hydrocortisone as compared to prednisolone, which is 5 fold more potent (17). The biological half-life of prednisolone is 8 hours (8 to 24 hours) as compared to 32 hours for dexamethasone (32 to 72 hours). Since one half-life of dexamethasone is equal to 4 half-lives of prednisolone, the biological equivalence of the two compounds is approximately 40 mg of prednisone to each mg of dexamethasone, and not 5 mg of prednisolone to 1 mg of dexamethasone as may be suggested by the relative equivalence. These derivations are approximate, since the absorption characteristics and biological half-lives of these compounds are variable from one patient to another.

Parenteral use of corticosteroids:

Intravenous administration of corticosteroids permits the use of large doses of corticosteroids, doses not feasible through oral formulation. Patients receive 500 to 1000 mg of methyl prednisolone daily for 3 to 5 days. The prednisolone is mixed in 100 ml of saline and administered over 2 to 4 hours. Some patients experience metallic taste in the mouth, but otherwise the drug is well tolerated. Although serious complications including acute myocardial infarction, acid peptic disease, pancreatitis, and delayed aseptic necrosis of the femur have all been reported with this treatment, such occurrences are fortunately rare (18). Nevertheless, patients should be informed of these possibilities. During treatment, daily electrolytes, glucose, and amylase should be obtained and abnormalities if any, corrected during treatment.

Are there any differences between oral and parenteral regimen ?

The Optic Neuritis Treatment Trial would suggest that such differences exist, at least for treatment of acute optic neuritis.This multicenter study  examined 3 treatment groups for patients with acute optic neuritis seen within 8 days:

Group 1. Methylprednisololone 250 mg IV q 6 hours for 3 days, followed by prednisolone 1 mg/kg tapered over a total duration of treatment of 14 days.

Group 2. Oral prednisolone 1 mg/kg , tapered over 14 days

Group 3. Placebo for 14 days. A total of 450 subjects were randomized into each of the 3 arms. 

Improvement of the visual acuity, visual fields, and color contrast sensitivity were observed in the IV group, evident as early as 2 weeks. By 6 months all groups were similar with regards to improvement of acuity, and 75% of all subjects had recovered vision to 20/20. What was however unexpected from this study was the fact that optic neuritis occurred in the opposite unaffected eye more often in the oral prednisolone group.

The recommendation after this study was therefore to use IV steroids, or no steroids at all, for treatment of acute optic neuritis. Since this study, there has been considerable interest as to whether the observed differences were a result of the differences in dose or route of administration. It would appear that the differences were based on the differences in dose rather than route since administration of 1 gm of methyl prednisolone by mouth was comparable in efficacy to the same dose administered IV. Further, it has been shown that disruption of the gastric mucosa does not occur to any greater degree by administration of the larger 1 gm dose as compared to 80 mg of prednisolone.


Multiple Sclerosis:

Agent Exacerbations:
I.V.Methyl Prednisolone 1gm. IV daily for 3-7 days, followed by an oral steroid taper with Prednisolone:
200mg x 4days then 100mg x 4 days then decreasing by 10mg daily until off, or Dexamethasone Taper:12mg x 4days then 8mg x 4days then 4mg x 4days.

Specific neuromuscular disorders

Muscle -                             Inflammatory myopathies
                                         Some Muscular dystrophy: Duchenne; ? LGMD 2D

Neuromuscular junction -     Myasthenia gravis
                                         Lambert-Eaton myasthenic syndrome

Nerve-                               Chronic immune demyelinating polyneuropathy (CIDP)
                                         Vasculitis & Vasculopathies

Usual doses:

Start at high dose then taper
Solu-Medrol (Methylprednisolone): 1 gram IV daily for 3 to 5 days
Prednisolone: Usually start at 50 mg to 100 mg per day (1 mg/kg/day): Single daily dose in am
Exception: Myasthenia gravis

Start at lower dose: 10 mg qd
Then gradually increase up to 50 mg qd
With respiratory or bulbar symptoms: Pre treat using Plasma Exchange Maintenance

Start at 1 gm/week IV for 1 month
Then 1 gm every 2 weeks for 2 months
Taper further by increasing time between doses Prednisolone
Start taper after: 3 to 6 months; or Clinical improvement
Taper slowly by 5 mg every 2 to 6 weeks

Risk of recurrent symptoms with taper: Varies with disease type
Myasthenia gravis: > 90% recurrence if steroids stopped
Inflammatory myopathy: ~ 50% recurrence risk
CIDP: Relapse more common
Disease course > 1 year
Adults > Children


Weight; Blood pressure; Blood glucose & electrolytes; Ocular exam

Advantages of corticosteroid therapy
Short onset of action (1 to 3 months)
Effective in majority of patients with specific disease indications
Can be used in pregnancy

Disadvantages of corticosteroid therapy

Transient initial severe exacerbation, usually after 1 to 3 weeks (2%).

Many are long-term side effects ( Fewer with intermittent Solumedrol);
Glucocorticoid side effects: Cushingoid features, Weight gain, Avascular necrosis, Osteoporosis, Myopathy, Myosin-loss, Type II atrophy, Diabetes, Acne, Striae, Hyperpsychosis, Pseudotumor cerebri, Glaucoma, Infection

Drug combinations:

Corticosteroids +Azathioprine: Steroid sparing effects . Cyclophosphamide: Additional efficacy, but high toxicity.


















































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