Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

Myelin sheaths cover many nerve fibers in the central and peripheral nervous system; they accelerate axonal transmission of neural impulses. Disorders that affect myelin interrupt nerve transmission; symptoms may reflect deficits in any part of the nervous system.

Myelin formed by oligodendroglia in the CNS differs chemically and immunologically from that formed by Schwann cells peripherally. Thus, some myelin disorders (eg, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, some other peripheral neuropathies—see Peripheral Nervous System Disorders: Peripheral Neuropathy) tend to affect primarily the peripheral nerves, and others affect primarily the CNS. The most commonly affected areas in the CNS are the brain, spinal cord, and optic nerves.

Multiple sclerosis is characterized by disseminated patches of demyelination in the brain and spinal cord. Common symptoms include visual and oculomotor abnormalities, paresthesias, weakness, spasticity, urinary dysfunction, and mild cognitive impairment. Typically, neurologic deficits are multiple, with remissions and exacerbations gradually producing disability. Diagnosis is by history of remissions and exacerbations plus objective demonstration of at least 2 separate neurologic abnormalities by clinical signs or test results, MRI lesions, or other criteria, depending on symptoms. Treatment includes corticosteroids for acute exacerbations, immunomodulatory drugs to prevent exacerbations, and supportive measures.

Multiple sclerosis (MS) is believed to involve an immunologic mechanism. One postulated cause is infection by a latent virus (unidentified), which, when activated, triggers a secondary immune response. An increased incidence among certain families and human leukocyte antigen (HLA) allotypes (HLA-DR2) suggests genetic susceptibility. MS is more common among people who spend their 1st 15 yr of life in temperate climates (1/2000) than in those who spend them in the tropics (1/10,000). Cigarette smoking also appears to increase risk. Age at onset ranges from 15 to 60 yr, typically 20 to 40 yr; women are affected somewhat more often.

Figure 1. Seen here in white matter is a large “plaque” of demyelination. The plaque has a grey-tan appearance. Such plaques are typical for multiple sclerosis (MS). These plaques lead to the clinical appearance of transient or progressive loss of neurological function. Since the disease is multifocal and the lesions appear over time, the clinical findings can be quite varied. (Click to magnify figure)

• Pathophysiology

Localized areas of demyelination (plaques) occur, with destruction of oligodendroglia, perivascular inflammation, and chemical changes in lipid and protein constituents of myelin in and around the plaques. Axonal damage is possible, but cell bodies and axons tend to be relatively preserved. Fibrous gliosis develops in plaques that are disseminated throughout the CNS, primarily in white matter, particularly in the lateral and posterior columns (especially in the cervical regions), optic nerves, and periventricular areas. Tracts in the midbrain, pons, and cerebellum are also affected. Gray matter in the cerebrum and spinal cord can be affected but to a much lesser degree.

• Symptoms and Signs

MS is characterized by varied CNS deficits, with remissions and recurring exacerbations. Exacerbations average about 3/yr, but frequency varies greatly. The most common initial symptoms are paresthesias in one or more extremities, in the trunk, or on one side of the face; weakness or clumsiness of a leg or hand; and visual disturbances (eg, partial loss of vision and pain in one eye due to retrobulbar optic neuritis, diplopia due to ocular palsy, scotomas). Other common early symptoms include slight stiffness or unusual fatigability of a limb, minor gait disturbances, difficulty with bladder control, vertigo, and mild affective disturbances; all usually indicate scattered CNS involvement and may be subtle. Excess heat (eg, warm weather, a hot bath, fever) may temporarily exacerbate symptoms and signs.

Mild cognitive impairment is common. Apathy, poor judgment, or inattention may occur. Affective disturbances, including emotional lability, euphoria, or, most commonly, depression, are common. Depression may be reactive or partly due to cerebral lesions of MS. A few patients have seizures.

Figure 2. Here is a demyelinated plaque in a patient with multiple sclerosis (MS). (Click to magnify figure)

• Cranial nerves:

Unilateral or asymmetric optic neuritis and bilateral internuclear ophthalmoplegia are typical. Optic neuritis produces loss of vision (ranging from scotomas to blindness), eye pain, and sometimes abnormal visual fields, a swollen optic disk, or a partial or complete afferent pupillary defect (see Optic Nerve Disorders: Optic Neuritis). Internuclear ophthalmoplegia results from a lesion in the medial longitudinal fasciculus connecting the 3rd, 4th, and 6th nerve nuclei. During horizontal gaze, adduction of one eye is decreased, with nystagmus of the other (abducting) eye; convergence is intact. Rapid, small-amplitude eye oscillations in straight-ahead (primary) gaze (pendular nystagmus) are uncommon but characteristic of MS. Vertigo is common. Intermittent unilateral facial numbness or pain (resembling trigeminal neuralgia), palsy, or spasm may occur. Mild dysarthria may occur, caused by bulbar weakness, cerebellar damage, or disturbance of cortical control. Other cranial nerve deficits are unusual but may be secondary to brain stem injury.

• Motor:

Weakness is common. It usually reflects corticospinal tract damage in the spinal cord, affects the lower extremities preferentially, and is bilateral and spastic. Deep tendon reflexes (eg, knee and ankle jerks) are usually increased, and an extensor plantar response (Babinski’s sign) and clonus are often present. Spastic paraparesis produces a stiff, imbalanced gait; in advanced cases, it may confine patients to a wheelchair. Painful flexor spasms in response to sensory stimuli (eg, bedclothes) may occur late. Cerebral lesions may result in hemiplegia, which sometimes is the presenting symptom.

Intention tremors, in which the limb oscillates during linear movement, may simulate cerebellar dysmetria (ataxic limb movements). Resting tremor may also occur and is especially obvious when the head is unsupported.

• Cerebellar:

In advanced MS, cerebellar ataxia plus spasticity may be severely disabling; other cerebellar manifestations include slurred speech, scanning speech (slow enunciation with a tendency to hesitate at the beginning of a word or syllable), and Charcot’s triad (intention tremor, scanning speech, and nystagmus).

• Sensory:

Paresthesias and partial loss of any type of sensation are common and often localized (eg, to the hands or legs). Various painful sensory disturbances (eg, burning or electric shocklike pains) can occur spontaneously or in response to touch, especially if the spinal cord is affected. An example is Lhermitte’s sign, an electric shocklike pain that radiates down the spine or into the legs when the neck is flexed. Objective sensory changes tend to be transient and difficult to demonstrate.

• Spinal cord:

Involvement commonly causes bladder dysfunction (eg, urinary urgency or hesitancy, partial retention of urine, mild urinary incontinence). Constipation, erectile dysfunction in men, and genital anesthesia in women may occur. Frank urinary and fecal incontinence may occur in advanced MS.

A variant of MS called optic neuromyelitis (Devic disease) causes acute optic neuritis, sometimes bilateral, plus demyelination of the cervical or thoracic spinal cord, resulting in visual loss and paraparesis. Another variant causes spinal cord motor weakness but no other deficits (progressive myelopathy).

• Diagnosis

MS is suspected in patients with optic neuritis, internuclear ophthalmoplegia, or other symptoms that suggest MS, particularly if deficits are multifocal or intermittent. Most diagnostic criteria for MS require a history of exacerbations and remissions plus objective demonstration by examination or testing of = 2 separate neurologic abnormalities. Brain and sometimes spinal MRI is done. If MRI plus the clinical data are inconclusive, additional testing may be necessary to objectively demonstrate separate neurologic abnormalities. Such testing usually begins with CSF analysis and, if necessary, includes evoked potentials.

MRI is the most sensitive imaging test for MS and can exclude other treatable disorders that may mimic MS, such as nondemyelinating lesions at the junction of the spinal cord and medulla (eg, subarachnoid cyst, foramen magnum tumors). Gadolinium-contrast enhancement can distinguish actively inflamed from older plaques. Alternatively, contrast-enhanced CT can be done. The sensitivity of MRI and CT is increased by giving twice the dose of contrast agent and delaying scanning (double-dose delayed scan).

Figure 3. Head MRI of a 35-year-old male with relapsing remitting multiple sclerosis revealing multiple high T2 signal intensity lesions. There is one large white matter lesion. These demyelinating lesions may sometimes mimic brain tumors due to associated edema and inflammation., Head MRI of the patient, performed three months later, shows a dramatic decrease in the size of lesions. (Click to magnify figure)

CSF IgG is usually increased as a percentage of CSF protein (normally < 11%), of CSF albumin (normally 10 yr. However, some patients, particularly men with onset in middle age, have frequent attacks and are rapidly incapacitated. Cigarette smoking may accelerate the course. Life span is shortened only in very severe cases.

Goals include shortening acute exacerbations, decreasing frequency of exacerbations, and relieving symptoms; maintaining the patient’s ability to walk is particularly important. Acute exacerbations that produce objective deficits sufficient to impair function (eg, loss of vision, strength, or coordination) are treated with brief courses of corticosteroids (prednisone 60 to 100 mg po once/day tapered over 2 to 3 wk, methylprednisolone 500 to 1000 mg IV once/day for 3 to 5 days). Although they may shorten acute attacks and perhaps slow progression, corticosteroids have not been shown to affect long-term outcome. However, methylprednisolone may delay progression from acute severe optic neuritis to MS.

Immunomodulatory therapy decreases frequency of acute exacerbations and delays eventual disability. Immunomodulatory drugs include interferons (IFNs), such as IFN-ß1b 8 million IU sc every other day, IFN-ß1a 6 million IU (30 µg) IM weekly, and IFN-ß1a 44 µg sc 3 times weekly. Common adverse effects include flu-like symptoms and depression (which tend to decrease over time), development of neutralizing antibodies after months of therapy, and cytopenias. Glatiramer acetate 20 mg sc once/day may be used. IFN-ß and glatiramer are not considered immunosuppressants. The immunosuppressant mitoxantrone, 12 mg/m2 IV q 3 mo for 24 mo, may be helpful, particularly for steadily progressive MS. Natalizumab, an anti-a4 integrin antibody, inhibits passage of leukocytes across the blood-brain barrier; given as a monthly infusion, it reduces number of attacks and new brain lesions, but marketing has been suspended pending evaluation of a possible association with progressive multifocal leukoencephalopathy. If immunomodulatory drugs are ineffective, monthly IV immune globulin may help. Immunosuppressants other than mitoxantrone (eg, methotrexate , azathioprine , mycophenolate, cyclophosphamide , cladribine) have been used for more severe, progressive MS but are controversial. (See also recommendations about corticosteroids and immunomodulatory therapies in Disease modifying therapies in multiple sclerosis, a practice guideline from the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the Multiple Sclerosis Council for Clinical Practice Guidelines.)

Spasticity is treated with escalating doses of baclofen 10 to 20 mg po tid to qid or tizanidine 4 to 8 mg po tid. Gait training and range-of-motion exercises can help weak, spastic limbs. Painful sensory neuropathy is usually treated with gabapentin 100 to 600 mg po tid; alternatives include tricyclic antidepressants (eg, amitriptyline 25 to 75 mg po at bedtime, desipramine 25 to 100 mg po at bedtime if amitriptyline has intolerable anticholinergic effects), carbamazepine 200 mg po tid, and opioids. Depression is treated with counseling and antidepressants. Bladder dysfunction is treated based on its underlying mechanism (see Voiding Disorders).

Encouragement and reassurance help. Regular exercise (eg, stationary biking, treadmill, swimming, stretching) is recommended, even for patients with advanced MS, because it conditions the heart and muscles, reduces spasticity, prevents contractures, and has psychologic benefits. Patients should maintain as normal and active a life as possible but should avoid overwork, fatigue, and exposure to excess heat. Vaccination does not appear to increase risk of exacerbations. Debilitated patients require measures to prevent pressure ulcers and UTIs; intermittent urinary self-catheterization may be necessary.

References

1. Bastianello S, Bozzao A, Paolillo A, et al: Fast spin-echo and fast fluid-attenuated inversion-recovery versus conventional spin-echo sequences for MR quantification of multiple sclerosis lesions. AJNR Am J Neuroradiol 1997 Apr; 18(4): 699-704.

2. Bornstein MB, Miller A, Slagle S, et al: A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurology 1991 Apr; 41(4): 533-9.
3. Comabella M, Balashov K, Issazadeh S, et al: Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest 1998 Aug 15; 102(4): 671-8.
4. Dangond F, Windhagen A, Groves CJ, Hafler DA: Constitutive expression of costimulatory molecules by human microglia and its relevance to CNS autoimmunity. J Neuroimmunol 1997 Jun; 76(1-2): 132-8.
5. European Study Group: Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS. Lancet 1998 Nov 7; 352(9139): 1491-7.
6. Fazekas F, Barkhof F, Filippi M, et al: The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 1999 Aug 11; 53(3): 448-56.
7. Jacobs LD, Cookfair DL, Rudick RA, et al: Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996 Mar; 39(3): 285-94.
8. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000 Sep 28; 343(13): 898-904.
9. Johnson KP, Brooks BR, Cohen JA, et al: Copolymer 1 reduces relapse rate and improves disability in relapsing- remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995 Jul; 45(7): 1268-76.
10. Johnson KP, Brooks BR, Cohen JA, et al: Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998 Mar; 50(3): 701-8.
11. Lucchinetti C, Bruck W, Parisi J, et al: Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000 Jun; 47(6): 707-17.
12. The IFNB Multiple Sclerosis Study Group and The University of British Columbia: Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995 Jul; 45(7): 1277-85.

13. The IFNB Multiple Sclerosis Study Group: Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double- blind, placebo-controlled trial. Neurology 1993 Apr; 43(4): 655-61.