multiple sclerosis

Multiple sclerosis

OSAMA RAGAB

introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by the breakdown of the insulating myelin sheath that covers the nerve axons in the CNS and subsequent degeneration of axons.

MS affects approximately 400,000 people in the USA and more than 2.1 million people worldwide, but the incidence has increased in the last five decades, particularly in women (3.6/100,000 person /years) compared to men (2.0/100,000 person /years)

introduction

Etiology1. Genetic

2. autoimmunity

3. Infection

4. Vitamin D

5. Cerebral venous insufficiency

6. Loss of old friends

Genetics The major histocompatibility complex (MHC) region on chromosome

6p21.32 is the first identified MS risk locus. HLA-DRB1*1501 allele conferring a ~3-fold risk increase. As well as

DRB1*1303 conferred further risk. IL7RA(encoding the interleukin receptor 7A) was initially assessed and

reported as a putative MS risk gene. IL2R were found to be significantly associated with relatively risk of α

MS. CYP27B1, a gene associated with vitamin D metabolism.

Genetics On the other hand, HLA-DRB1*14 carries such a protective effect that it

completely abrogates the increased risk of HLA-DRB1*15. GWAS implicate genes coding for cytokine pathways (CXCR5, IL-2RA, IL-

7R, IL-7, IL-12RB1, IL-22RA2, IL-12A, IL-12B, IRF8, TNFRSF1A, TNFRSF14, TNFSF14) .

Costimulatory (CD37, CD40, CD58, CD80, CD86, CLECL1) and signal transduction (CBLB, GPR65, MALT1, RGS1, STAT3, TAGAP, TYK2).

Autoimmunity

Infection

little direct evidence supports the concept of a role for viral infection. Innumerable efforts to culture a virus from autopsy-derived or biopsy material have yielded no consistent result.

human T-cell lymphotropic virus type 1 [HTLV1]) have proven negative.

Human herpesvirus 6 (HHV6), Epstein-Barr virus (EBV), and Chlamydia pneumoniae have been the focus of interest.

High serum levels of EBV antibodies have also been associated with an increased risk of MS.

Geographical distribution of MS

Vitamin D

MS patients typically have lower serum 25(OH)D levels than healthy controls .

Polymorphisms in the vitamin D receptor (VDR) gene have been of particular interest.

candidate gene approach include two vitamin D metabolism-related genes, CYP2R1 [which encodes the enzyme responsible for the conversion of vitamin D to 25(OH)D] and DBP/GC (encoding the vitamin D-binding protein)

these inverse associations could also be explained by a direct effect of UVB radiation, which has immunosuppressive effects independent from vitamin D.

Venous insufficiency

Zamboni and colleagues proposed that multiple sclerosis is caused by abnormalities in the direction and pathway of cerebral venous flow, leading to deposition of iron in the brain, which triggers an autoimmune reaction.

They reported that patients with multiple sclerosis had a higher frequency of abnormalities of anatomy and flow in the internal jugular, deep cerebral, vertebral and azygous veins than individuals without multiple sclerosis had.

Venous insufficiency

Loss of old friends

Leibowitz and co-workers proposed that the prevalence of MS was linked to a high sanitation level during childhood.

Epidemiological data demonstrating an inverse relationship between the prevalence of autoimmune diseases and parasite infections, and more specifically between MS and the helminth Trichuris trichuria.

There is decrease production of IL-12, TNF- and IL-1 and increased α βproduction of TGF- and IL-10 in peripheral blood mononuclear cells β(PBMC's) and increased proliferation of CD4+CD25high regulatory T-cells (Tregs) in infected person.

Loss of old friends

Clinical picture

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.

2.Secondary progressive MS: may develop in some patients with relapsing–remitting disease

3.Primary progressive MS: affects approximately 10% of MS patients. Symptoms continue to worsen gradually from the beginning.

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.

Clinical picture

What Is the Composition of the MS Plaque

Multiple sclerosis plaques may be characterized as active or inactive .

Macrophages are especially plentiful in active lesions which are hypercellular and contain patchy infiltrates of autoreactive T cells and antigen-nonspecific monocytes and macrophages within a zone of myelin loss .

Macrophages and lymphocytes form prominent perivascular cuffs and invade the parenchyma, whereas plasma cells and B cells tend to concentrate in the perivascular region only

What Is the Composition of the MS Plaque

Chronic plaques display well-demarcated areas of hypocellularity with myelin pallor or loss .

There are varying degrees of axonal loss, usually most obvious in the lesional center .

There is typically a persistent but minor inflammatory response.

There are few or no oligodendrocytes.

Clinical picture

Cognitive Impairment.

34% to 65% of patients with MS have cognitive impairment.

The domains of verbal memory and attention/speed of information processing were the most affected.

Comorbid depression, anxiety disorders, and emotional lability may further affect cognitive performance.

Lesions located in frontal and parietal lobes showed stronger correlations with tasks of processing speed, attention, and verbal memory.

Clinical picture

Affective Disorders.

Depression is the most common manifestation and is in part secondary to the burden of having to cope with a chronic disease.

Suicide rates are higher in patients with MS than in the general population.

emotional “dyscontrol” is quite common, and patients oscillate frequently between sad and happy states, at times without precipitant.

Clinical picture

Impairment of Visual Pathways

Optic neuritis (ON) is the most frequent type of involvement of the visual pathways, usually presenting as an acute or subacute unilateral syndrome.

Bilateral simultaneous ON is rare in MS.

The Uhthoff phenomenon refers to a recurrence of a neurological symptom (e.g., visual blurring) following an increase in body temperature.

Clinical picture

Impairment of Ocular Motor Pathways

the involved nerves are, in decreasing order of frequency, cranial nerves VI, III, and (rarely) IV.

acquired pendular nystagmus, in which there are rapid small-amplitude pendular oscillations of the eyes in the primary position, resembling quivering jelly.

Internuclear ophthalmoplegia (INO), Convergence is preserved. When present bilaterally, it is usually coupled with vertical nystagmus on upward gaze.

One and half syndrome.

Clinical picture

Impairment of Other Cranial Nerves.

Facial myokymia, a fine, undulating wavelike facial twitching, and hemifacial spasm.

Unilateral facial paresis can occur, but taste sensation is almost never affected.

Vertigo is a reported symptom in 30% to 50% of patients with MS and is commonly associated with dysfunction of adjacent brainstem or cranial nerves.

Malfunction of the lower cranial nerves is usually of the upper motor neuron type (pseudobulbar syndrome)

Clinical picture

Impairment of Sensory Pathways

The sensory features can reflect spinothalamic, posterior column, or dorsal root entry zone lesions. The sensory symptoms are commonly described as numbness, tingling, pins and needles.

The most frequent sensory abnormalities on clinical examination are varying degrees of impairment of vibration and joint position sense.

Brown-Séquard syndrome.

the “numbclumsy hand” syndrome is a characteristic but uncommon

Clinical picture

Impairment of Motor Pathways.

Paraparesis or paraplegia occurs more frequently than significant weakness in the upper extremities.

Amyotrophy, when observed, most frequently affects the small muscles of the hand; lesions of the motor root exit zones may produce muscle denervation secondary to axon loss.

Clinical picture

Impairment of Cerebellar Pathways

gait imbalance, difficulty performing coordinated actions with the arms, and slurred speech.

dysmetria, decomposition of complex movements, and hypotonia, most often observed in the upper extremities.

An intention tremor

Ocular findings of nystagmus, ocular dysmetria, and frequent refixation saccades.

Speech can be scanning or explosive in character.

In severe cases, complete astasia (inability to stand),

Clinical picture

Impairment of Bladder, Bowel, and Sexual Functions

urinary urgency, usually the result of uninhibited detrusor contraction, reflecting a suprasegmental lesion.

As the disease progresses, urinary incontinence due to urgency becomes more frequent.

With involvement of sacral segments of the spinal cord, symptoms of bladder hypoactivity may evolve (e.g., decreased urinary flow, interrupted micturition, incomplete bladder emptying).

Clinical picture

Impairment of Bladder, Bowel, and Sexual Functions

An atonic dilated bladder that empties by overflow results from loss of perception of bladder.

A dyssynergic voluntary sphincter that interrupts bladder emptying will lead to frequent, small-volume urinations combined with a large postvoid residual.

Constipation is more common than fecal incontinence.

Sexual dysfunction, although frequently overlooked, occurs commonly in MS. Approximately 50% of patients become completely sexually inactive because of their disease, and an additional 20% become less sexually active.

Tumefactive MS

Tumefactive MS is an acute tumor-like MS variant in which some patients with demyelinating disease present with large (>2 cm) acute lesions, often associated with edema or ring enhancement .

There may be mass effect, with compression of the lateral ventricle and shift across the midline. Although there is no consensus regarding nomenclature.

Tumefactive MS

The clinical abnormalities in such patients are variable; they may be very slight even in a patient with a massive lesion, while confusion, hemiparesis, or neglect syndrome can be seen in another patient with a lesion that appears no different.

Typically, much of the T2-bright lesion volume on brain MRI is due to edema and may be rapidly responsive to glucocorticoid treatment. However, radiologic improvement with glucocorticoids can also occur with glioma or with central nervous system lymphoma and is therefore not a useful diagnostic criterion.

Biopsy is often required.

Clinical picture

Clinical picture

Prognosis. Sex: benign course in women than in men. Age at onset: Average is 29 to 32 years. Onset at an early age is a favorable

factor, whereas onset at a later age carries a less favourable. Initial disease course: Relapsing form of the disease is associated with a

better prognosis than progressive disease Initial complaints: impairment of sensory pathways or ON has been found

in several studies to be a favorable prognostic feature, whereas pyramidal and particularly brainstem and cerebellar symptoms carry a poor prognosis.

Magnetic resonance imaging

3 of 4

1 Gd+ or 9 T2-hyperintense lesions if there is no enhancing lesion

At least one infratentorial lesion

At least one juxtacortical lesion

At least 3 periventricular lesions

MRI criteria dissemination in spaceBarkhof et al criteria

MAGNETIC RESONANCE SPECTROSCOPY

In active, newly formed MS plaques, NAA is slightly decreased and Cre, Cho, and mI are increased. Lactate (Lac) peak is also increased, suggesting energy failure. Over time, the initial surge in lipids, Cho, Lac, and Cre may return to near normal.

In contrast to active plaques, chronic MS lesions show considerable reduction in NAA, normal glutamate peaks, and elevation in mI. Interestingly

Magnetization Transfer Imaging

Demyelination is visualized as a reduced proton exchange, or a decrease in the magnetization transfer ratio (MTR), whereas an elevated proton exchange, or increased MTR, is evidence of possible remyelination or resolution of edema.

Diffusion tensor imaging

Diffusion tensor imaging allows measurement of fractional anisotropy, which reflects the degree to which the diffusion of water molecules follows one direction versus many directions.

This technique is useful for assessing the integrity of white matter tracts, which normally have a high degree of anisotropy due to their linear arrangement and the preferred diffusion of water along the long axis of the myelinated fibers .

Injury to nerve axons or myelin sheaths permits increased diffusion of water across the white matter tract and thereby decreases fractional anisotropy

Diffusion tensor imaging

Axial flair image (A) show two plaques in the internal capsule, one in the anterior limb and one in the posterior limb. Diffusion tensor fractional anisotropy map (B) shows asymmetric hypointensity (decreased anisotropy) in these regions

Cerebrospinal fluid analysis

The CSF appearance and pressure are grossly normal in MS.

The total leukocyte count is normal in two-thirds of patients, exceeds 15 cells/microL in <5 percent, and only rarely exceeds 50 cells/microL (a finding that should raise suspicion of another etiology).

Lymphocytes are the predominant cell type, the vast majority of which are T cells.

CSF protein (or albumin) level is usually normal.

Cerebrospinal fluid analysis

An abnormality of CSF IgG production as measured by the IgG index or IgG synthesis rate is found in 90 percent of clinically definite MS patients .

Oligoclonal bands — OCBs are found in up to 95 percent of patients with clinically definite MS .

OCBs represent limited classes of antibodies that are depicted as discrete bands on agarose gel.

The presence of OCBs is not equivalent to a diagnosis of MS.

Antimyelin antibodies — Initial studies suggested that antibodies to myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) were potential markers of MS .However, subsequent evidence suggests that these antibodies are not associated with an increased risk of progression to MS or with MS disease activi

Isoelectric focusing in an agarose gel at stable pH (range 5.0–9.5) demonstrating the presence of oligoclonal bands (arrows) in the CSF (above) and not the serum (below).

The oligoclonal bands are different clones of IgG that have migrated electrophoretically in the stationary pH gradient until a steady state is reached.To be positive, two or more oligoclonal bands must be detected in the CSF that are not present in the serum of the patient.

Evoked potentials

Evoked potentials are the electrical events generated in the central nervous system by peripheral stimulation of a sensory organ.

The three most frequently used evoked potentials are somatosensory evoked potentials (SSEP), visual evoked responses (VER), and brainstem auditory evoked potentials (BAEP). Patients with clinically definite MS have abnormal VERs in 50 to 90 percent of cases .

Treatment

IVMP 20 to 30 mg/kg/day for 5 days. A subsequent oral tapering should be restricted to patients with:-

i) insufficient resolution of symptoms after steroid.

ii) recurrence of symptoms after steroid discontinuation. Steroid tapering continued usually not exceeding 2 to 3 weeks .

I- Treatment of relapses: 1) Corticosteroids:

3) IV immunoglobulins: IVIg 0.4 g/kg daily for 5 days in acute demyelinating attacks that do not improve after high dose of steroid ٭.

2) Plasma exchange: indicated in i) Life-threatening acute demyelination. ii) Recurrence of symptoms during or after steroid therapy ٭٭.

Management

Oral medication

Fingolimod ( 0,5 mg daily ) act on s1p receptor prevent egress of activated lymphocyte to circulation from lymph node.

Fumaric acid ( 240 mg twice) it activate transcriptional factor nrf2. Teriflunamide ( 14 mg ) inhibit pyrimidine synthesis. Cladribine ( 0.07 mg / kg ) purine nuclside analogue. Laquinamide ( 0.6 mg ) shift Th1 to Th2 response

Monoclonal antibodies

Natalizumab ( 300 mg /28 day ) act on integrin ( VLA4) . Rituximab ( 375mg /m²/week ) for 2 months , act on CD2O of B cells. Daclizumab act on CD25 of both T&B cells. Almetuzumab act on CD52 of both T& B cells. Ocrelizumab act on CD20 . Mastinab it bind to tyrosine kinase of mast cells

Chemotherapy Cyclophosphamide

The therapy may be administered orally( 1.5 mg/kg) or intravenously.

The most widely used regimen is monthly pulsed therapy with 800 mg/m2 administered monthly for 1 year, followed by bimonthly treatments in those who are responders, although numerous other regimens have been proposed, including the use of combined treatment with methylprednisolone.

Dose adjustments are made based on the peripheral white blood cell (WBC) nadir acquired on the 14th day following treatment The rationale of this adjustment is to attenuate the peripheral WBC counts with levels between 1500 and 2000 WBC/mm3.

Chemotherapy METHOTREXATE

Methotrexate inhibits dihydrofolate reductase, an enzyme responsible for the conversion of dihydrofolate into tetrahydrofolate. Tetrahydrofolate and its derivatives are essential for purine and thymidylate synthesis and cell proliferation and growth.

Dose 7.5 mg / week IM.

Chemotherapy AZATHIOPRINE

In some instances,considered as a first-line treatment for those unwilling to use IFN-b or glatiramer acetate, despite somewhat conflicting data.

The medication targets activation, proliferation, and differentiation of fast-growing cells, including T and B cells, through inhibition of purine synthesis.

Dose up to 2.5 mg /kg daily.

Symptomatic treatment

Spasticity• Attend to any factors which may exacerbate spasticity, such as noxious stimuli due to urinary tract infection, infected pressure sores or ulcers, tight clothing, or an uncomfortable orthotic.

• Educate patients to understand and manage their spasticity.

• Correct posture: avoid positions which favor the pattern of spasticity.

• Physiotherapy

Pharmacology:

Oral agents:

–– Tizanidine, an L2 alpha adrenergic antagonist.

–– Baclofen, 5 mg bd, increasing slowly to 10–25 mg three times daily if tolerated and required

–– Diazepam 5–10 mg three times daily.

–– Dantrolene.

–– Gabapentin.

• Intramuscular injections of botulinum toxin A

• Intrathecal baclofen: • Rarely, nerve blocks are used


Bladder dysfunction• Detrusor hyper-reflexia:

• Clean intermittent self-catheterization (CISC) is the most effective.

• Anticholinergic agents (reduce urgency but may increase residual volume):

–– Oxybutynin hydrochloride 5 mg tablets,

25–5.0 mg every 6–8 hours.

–– Propantheline bromide 15 mg, four times daily.

–– Amitriptyline 25–100 mg daily.

• Intravesical botulinum toxin is an increasingly promising technique.


Fatigue• Psychologic counseling.

• Amantadine 100 mg in the morning and afternoon can help in some cases.

• 4-Aminopyridine (fampridine), and 3-4-diaminopyridine, a potassium channel blocking agent, may have a role.


Tremors and Ataxia• Clonazepam 0.5–2.0 mg two or three times daily.• Ondansetron, a 5-hydroxytryptophan-3 (5-HT3) antagonist, 8 mg IV.• Carbamazepine.• Gabapentin.• Isoniazid and pyridoxine. • Propranolol.• Buspirone.• Surgery. Deep brain stimulation appears promising for tremor, but not ataxia,

in MS.


Cognitive dysfunction and depression

in some cases, cognitive rehabilitation.

There is emerging evidence for acetylcholinesterase inhibitors such as donepezil.

The treatment of depression is similar to that of a patient who does not have MS, and includes psychologic counseling and serotonin reuptake inhibitors such as tricyclic antidepressants. However, particular attention needs to be paid to adverse effects, as they may exaggerate existing problems such as sexual dysfunction.


Visual dysfunction

• Monocular blindness or scotoma, diplopia and oscillopsia: this is difficult to manage, but referral to low vision clinics can be helpful.

• Botulinum toxin injections of oculomotor muscles may reduce persistent oscillopsia.

• Acquired pendular nystagmus may respond to converging prisms and isoniazid (and possibly gabapentin).


multiple sclerosis

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