Demyelinating Disorders

Published on 10/02/2015 by admin

Filed under Emergency Medicine

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 1670 times

98 Demyelinating Disorders

Presenting Signs and Symptoms

In general, all the demyelinating disorders are characterized by an abrupt episode of loss of function. Depending on the area of the brain or nervous system affected, the patient may have sensory, motor, or autonomic symptoms.

Multiple Sclerosis

In MS, the initial attack occurs abruptly (minutes to hours) from a single lesion. These attacks last between 6 and 8 weeks. Recovery between bouts of demyelination can be incomplete or complete, depending on the amount of remyelination. Any part of the central nervous system can be affected. In decreasing order of frequency, the patient may exhibit optic neuritis, paresthesias in a limb, diplopia, trigeminal neuralgia, urinary retention, vertigo, or transverse myelitis. Depending on the spinal cord level, transverse myelitis can also cause loss of bladder or bowel function.

Ocular findings are the most common initial symptom. Optic neuritis is manifested as subacute monocular vision loss, although it can affect both eyes, and pain exacerbated with eye movement. It is the initial symptom in 25% and ultimately affects 50% of patients.1 The course usually progresses over a period of 2 weeks and may be include headache, retroorbital or periocular pain, and alterations in color vision and visual fields. Slit-lamp examination may demonstrate cell and flare in the anterior chamber. The optic disk is frequently swollen on initial evaluation. In addition to optic neuritis, the patient may have an afferent pupillary defect (Marcus Gunn pupil, or decreased pupillary constriction on direct light confrontation but a normal consensual response) or intranuclear ophthalmoplegia, which is characterized by dysconjugate gaze with limited adduction of one eye and nystagmus in the abducting eye on lateral gaze as a result of a lesion involving the medial longitudinal fasciculus.

Sensory symptoms in patients with MS usually include numbness, tingling, pins and needles sensation, and tightness and coldness of the limbs and trunk. Radicular pain and itching may also occur. Symptoms result from involvement of the spinothalamic, posterior column, and dorsal nerve roots. The loss of vibration sense is often most prominent. Ataxia is uncommon at the onset of MS, but it occurs to some degree in most patients. Exacerbation of sensory symptoms can occur frequently and in different patterns with a patchy distribution. Patients may note either paresthesias or loss of sensation.

Sensitivity to heat is a characteristic complaint. Exercise, fever, a hot bath, or other activities that raise body temperature may result in the appearance of new symptoms or the recurrence of old symptoms. These events occur as a result of a temperature-induced conduction block across partially demyelinated fibers. Symptoms resolve when body temperature returns to normal.

In addition to loss of sensation, patients may also report “positive” symptoms. In addition to causing a slowing of conduction, demyelination may result in ectopic impulses with resultant abnormal signal transmission and abnormal mechanical sensitivity. These aberrant signals can produce the Lhermitte sign—an electric-like tingling or vibrating sensation in the torso or extremities with neck flexion. The patient may also report flashes of light (phosphenes) and paroxysmal symptom, including trigeminal neuralgia, ataxia, and dysarthria or painful tetanic posturing of the limbs triggered by touch or movement.

Motor weakness may occur in any pattern, including paraparesis, hemiparesis, and monoparesis; the lower extremities are usually affected more than the upper ones. Upper motor neuron dysfunction accompanied by spasticity and increased reflexes may also be present. Transverse myelitis with ascending weakness and numbness below the level of the lesion can occur as an initial symptom.

Autonomic symptoms are a frequent finding. Patients have difficulty with bladder function, including frequency and urgency, and may experience urge incontinence from bladder spasticity or hesitancy, retention, and overflow incontinence from poor signal conduction. Constipation is the most common bowel complaint. This autonomic dysfunction is frequently very embarrassing and distressful.

Normal disease progression is variable: MS may remain indolent or occur in a progressive manner, with steady accumulation of neurologic deficits in the absence of clearly defined exacerbations. Typically, acute exacerbations are followed by partial or complete resolution. New neurologic deficits develop over the course of several hours or days, remain stable for a few days to a few weeks, and then gradually improve.

With repeated exacerbations, permanent neurologic deficits tend to develop. Patients usually have symptom-free intervals of months or years between attacks. Patients who initially have relapsing-remitting disease (two or more episodes lasting more than 24 hours separated by more than 1 month) and who then enter a progressive phase are said to have secondary progressive disease (initial exacerbations and remissions followed by slow progression over at least a period of 6 months), whereas those whose symptoms are progressive from the onset are said to have primary progressive disease (slow or stepwise progression over a period of at least 6 months). About 15% of patients have primary progressive disease; of those who initially have relapsing-remitting disease, 30% to 50% will experience progressive symptoms during the first 10 years.

Differential Diagnosis and Medical Decision Making

The differential diagnosis of demyelinating diseases includes conditions that cause progressive weakness. In due course the diagnosis of a demyelinating disorder becomes clear because few disorders relapse and remit over time. The role of the EP is to exclude other diseases that need immediate treatment.

Clinical factors that suggest a diagnosis other than MS (Table 98.1) include normal findings on neurologic examination, aphasia, predominance of pain, abrupt hemiparesis, quick (seconds or minutes) resolution of symptoms, and age younger than 10 or older than 50 years.

Table 98.1 Differential Diagnosis of Multiple Sclerosis

DISEASE/SYSTEM IMPORTANT FACTORS
Seizures, syncope, or dementia Present diffusely or globally; MS is usually focal; consider Todd paralysis in seizure patients
SLE Neurologic findings normally occur in patient with a known diagnosis of SLE
Sarcoid CNS and pulmonary involvement normally occurs in patients with known disease
Lyme disease Can mimic MS; look for tick exposure, travel history, and Lyme disease titers
CNS infection Intracranial abscess, meningitis/encephalitis, or epidural abscess can produce focal findings
Bleeding (CNS) Subdural, subarachnoid, intraparenchymal, or epidural hemorrhage can produce focal findings
Neoplasm Usually progressive course with a more insidious onset
Vascular Patients with thrombosis, embolism, or vasculitic conditions do not usually have resolution of symptoms
Metabolic Vitamin B12 deficiency, hypoglycemia, hyperglycemia (hyperosmolar)
Neurologic Migraine headache, postictal state, Bell palsy
Psychiatric Diagnosis of exclusion; includes conversion reaction

CNS, Central nervous system; MS, multiple sclerosis; SLE, systemic lupus erythematosus.

The diagnosis is usually made from the clinical signs and symptoms; MRI and other laboratory tests play a supporting role. Diagnosis requires evidence of dissemination of lesions in time and space and careful exclusion of other causes. The patient should have had more than one episode of neurologic dysfunction and evidence of white matter lesions in more than one part of the central nervous system or a change in a previous lesion. Although it is possible for a neurologist to diagnoses MS during an initial attack, provided that two clinical lesions are present and with corroborating laboratory testing, it is prudent for the EP to use a more conservative approach that requires two distinct attacks.

The EP should consider the diagnosis in a young adult with a history of two or more clinically distinct episodes of central nervous system dysfunction or the presence of highly suggestive symptoms (optic neuritis or intranuclear ophthalmoplegia). In 2005, the McDonald criteria revised the 2001 guidelines of the International Panel on MS2 to incorporate specific MRI findings and reaffirm the need for separation of clinical events and lesions in space and time. Diagnostic confidence is based on whether the criteria are fully met (diagnosis of MS), partially met (possible MS), or not met (not MS). Table 98.2 lists characteristic factors differentiating demyelinating disorders.

Differential diagnoses for optic neuritis include anterior ischemic optic neuropathy, which is usually painless and found in patients older than 50 years; hereditary diseases such as Leber hereditary optic neuropathy; and toxic or nutritional optic neuropathies.

Transverse myelitis may superficially resemble GBS, but its asymmetric involvement, definite sensory level, lack of upper extremity involvement, urinary incontinence symptoms, and CSF pleocytosis make the diagnosis of GBS less likely. The differential diagnosis includes other causes of acute myelopathy such as compression of the cord by an extradural structural lesion, spinal cord neoplasms, ischemia, and systemic lupus erythematosus.

Heavy metal poisoning can also mimic GBS, but it is usually preceded by a gastrointestinal phase with vomiting and diarrhea. As discussed previously, transverse myelitis can superficially resemble this syndrome.

Diagnostic Testing

Findings on routine laboratory tests are usually normal in patients with myelinating disorders, including MS, transverse myelitis, and GBS. Because the respiratory muscles are frequently affected in GBS, measurement of forced vital capacity (FVC) is essential to determine disposition.

Most cases of optic neuritis are diagnosed clinically. In questionable cases of optic neuritis, serum testing (erythrocyte sedimentation rate, angiotensin-converting enzyme, rapid plasma reagin, thyroid function testing, and antinuclear antibody studies) can be ordered to exclude other causes of optic neuropathy.

Magnetic Resonance Imaging

MRI permits the exclusion of many diseases that mimic MS and identifies certain lesions that are hyperintense on T2-weighted or proton density imaging and hypointense or isointense on T1-weighted imaging. Typical lesions are ovoid and periventricular, with the long axis perpendicular to the ventricle, but lesions may appear anywhere in the white matter. Although MRI is extremely sensitive in detecting white matter lesions in patients with MS, it is not very specific because many other diseases produce multiple white matter lesions. Useful features for increasing the predictive value of MRI for the diagnosis of MS include the presence of three or more white matter lesions, lesions that abut the body of the lateral ventricles, infratentorial lesions, lesions larger than 5 mm in diameter, and lesions that demonstrate gadolinium enhancement.

MRI is extremely useful for confirming the presence of an intramedullary lesion at the level in the spinal cord commensurate with the symptoms of transverse myelitis. The lesions are typically hyperintense on T2-weighted imaging; they involve the majority of the cross-sectional area of the cord over several segments and may be enhanced with contrast agents. The lesions may cause swelling of the spinal cord. Gadolinium-enhanced MRI may show abnormal enhancement of the nerve roots in the region of the conus medullaris and cauda equina.3

MRI is also useful for diagnosing optic neuritis and evaluating for concomitant MS. Gadolinium enhancement may demonstrate optic nerve involvement. In questionable cases, visually evoked potentials may demonstrate prolonged latency.

Treatment

For all demyelinating conditions, the EP’s goal is to reduce the current demyelinating episode while ensuring that the ABCs (airway, breathing, and circulation) are maintained. Because inflammation is a central component of demyelination, corticosteroids are frequently used; their effectiveness in patients with GBS and optic neuritis is questionable. Preventing and aggressively treating fever are important because an increased core temperature can worsen the demyelination.

Multiple Sclerosis

Treatment of MS can be discussed in terms of the management of acute relapses, prevention of relapses as a modification of the disease process, and management of symptoms and fixed neurologic deficits. High-dose pulsed corticosteroid therapy is indicated for exacerbations of acute relapses that adversely affect the patient’s function. Intravenous (IV) methylprednisolone at doses of 0.5 to 1 g daily for 5 days reduces the maximal neurologic signs and hastens the resolution of associated fatigue. A controversial study by Sellebjerg et al. supports the use of oral methylprednisolone (500 mg daily for 5 days with a 10-day tapering period).4

In patients with relapsing-remitting MS, disease-modulating drugs reduce the frequency of attacks, the rate of increase in lesions seen on MRI, and the accumulation of disability. In patients with relapsing disease of mild to moderate severity, interferon beta-1b, given subcutaneously every other day, reduced the year-on-year relapse rate by one third and severe attacks by one half. The effect was maintained for up to 5 years.5,6 In another study, interferon β1b reduced MRI contrast-enhanced lesions by 1.6%, as opposed to a 15% increase in those receiving placebo. The number of enlarging or new lesions was also significantly reduced.7 Antibodies developed in 35% of patients taking interferon β1b, but there is a lack of consistent effect of antibodies on clinical outcome. Additionally, these antibody levels were found to have disappeared in the majority of patients after 8 years of treatment.8,9

Interferon β1a produced similar benefits when given intramuscularly three times per week, with a 17% reduction in the relapse rate. When compared with weekly, low-dose interferon β1a, high-dose interferon β1a given three times per week demonstrated a 32% relative reduction in steroid use to treat relapses.10

Glatiramer, a synthetic random compound composed of four amino acids, is found in myelin. Its exact mechanism is unknown, but it is believed that glatiramer acetate binds to the major histocompatibility complex class II antigen and induces organ-specific T helper type 2 cell responses, thus converting proinflammatory T cells to antiinflammatory agents.11 Treatment with glatiramer reduces the relapse rate by 30% and may delay disease progression.12

Natalizumab, a monoclonal antibody against α4 integrins, is effective for relapsing-remitting MS. The reduction in annualized relapse rates with natalizumab is similar to that with glatiramer or interferon β.13 However, it is not a first-line agent because it can cause progressive multifocal leukoencephalopathy in 0.1% of cases.14

Mitoxantrone is an anthracenedione, antineoplastic agent approved for the relapsing-remitting and progressive forms of MS. Cardiotoxicity, acute leukemia, and questionable efficacy limit it to treatment failures or cases of rapidly progressive MS.

Fingolimod, the first oral treatment option for MS approved by the Food and Drug Administration, is a sphingosine analogue that blocks lymphocyte release from lymph nodes through interaction with the sphingosine 1-phosphate receptor. Fingolimod can significantly reduce relapse rates when compared with interferon β1a. However, fingolimod is associated with life-threatening infections, bradycardia, atrioventricular block, tumor development, and macular edema.15

Specific therapies for relief of symptoms are provided in Table 98.3.

Table 98.3 Symptomatic Treatment of Multiple Sclerosis

SYMPTOM TREATMENT OPTIONS
Fatigue Amantadine, pemoline, methylphenidate, modafinil, or selective serotonin reuptake inhibitor
Weakness Steroids, potassium channel blocker
Loss of balance or coordination, tremor, ataxia Clonazepam for tremor, steroids for balance
Sexual dysfunction Sildenafil, intracavernosal prostaglandins (for erectile dysfunction)
Vertigo Meclizine, prochlorperazine, diazepam, metoclopramide
Paroxysmal symptoms (itching, burning, twitching, Lhermitte sign) Carbamazepine, phenytoin, tricyclic antidepressants, low-dose antipsychotics, gabapentin
Bladder urgency Oxybutynin, tolterodine, imipramine, hyoscyamine, propantheline
Bladder dyssynergia Phenoxybenzamine, clonidine, terazosin
Bladder retention Intermittent catheterization, bethanechol
Spasticity (commonly increased tone in the lower extremities) Baclofen, diazepam, tizanidine, clonazepam, clonidine (adjunctive to baclofen), dantrolene
Paresthesias Amitriptyline, carbamazepine, gabapentin, corticosteroids if disabling
Optic atrophy, blurred vision, central scotomata Intravenous methylprednisolone for acute optic neuritis
Intranuclear ophthalmoplegia Corticosteroids
Ataxia Clonazepam, gabapentin
Paroxysmal pain Carbamazepine, phenytoin, misoprostol (trigeminal neuralgia)
Dysesthetic pain Amitriptyline, phenytoin, gabapentin, valproic acid, carbamazepine, baclofen

Transverse Myelitis

Corticosteroids and plasma exchange may be beneficial in the treatment of transverse myelitis.16 In a small case series, patients treated with steroids were able to walk after a median time of 23 days versus 97 days for historical controls.17 Plasma exchange is often used for those with more severe disease (e.g., unable to walk) who fail to improve with IV steroid therapy.18 The prognosis for transverse myelitis is variable.

Optic Neuritis

IV methylprednisolone (1 g/day for 3 days) followed by oral prednisone (1 mg/kg/day for 11 days with a 4-day taper) and interferon β1a (30 mcg intramuscularly once a week) for patients at high risk for MS based on MRI has been shown to hasten recovery of vision in patients with optic neuritis.19 However, this therapy shows little residual benefit at 1 year. Additionally, oral prednisone therapy alone was found to actually increase the recurrence rate.20 Regardless of therapy, most patients recover their vision within a month.

Follow-up, Next Steps in Care, and Patient Education

All patients with a first episode of a demyelination disorder merit neurology consultation. Although outpatient therapy is possible for a subset of these patients, this decision is best left to the neurologist. As discussed previously, the typical course of MS is a relapsing-remitting pattern. During an acute exacerbation, the patient is frequently admitted for IV steroid therapy, but oral treatment is possible.

Hospital admission is required for GBS, and FVC measurement typically guides selection of the appropriate level of care. The majority of patients are hospitalized for a month or longer, and with careful attention to respiratory function, mortality is now less than 5%.

Patients should undergo ophthalmology and neurology evaluation for manifestations of optic neuritis. If steroid therapy is needed, hospital admission is necessary because steroids may worsen the clinical outcome.

References

1 Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006;354:1273–1280.

2 Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald criteria.”. Ann Neurol. 2005;58:840–846.

3 Patel H, Garg BP, Edwards MK. MRI of Guillain-Barré syndrome. J Comput Assist Tomogr. 1993;17:651–652.

4 Sellebjerg F, Frederiksen JL, Nielsen PM, et al. Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology. 1998;51:529–534.

5 Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277–1285.

6 Arnason BG. Long-term experience with interferon beta-1b (Betaseron) in multiple sclerosis. J Neurol. 2005;252(Suppl 3):iii28–iii33.

7 Miller DH, Molyneux PD, Barker GJ, et al. Effect of interferon 1-b on magnetic resonance imaging outcomes in secondary progressive multiple sclerosis: results of a European multi-center, randomized, double-blind, placebo-controlled trial. European Study Group on Interferon-beta 1b in Secondary Progressive Multiple Sclerosis. Ann Neurol. 1999;46:850–859.

8 Polman C, Kappos L, White R, et al. European Study Group in Interferon Beta-1b in Secondary Progressive MS. Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b. Neurology. 2003;60:37–43.

9 Rice GP, Paszner B, Oger J, et al. The evolution of neutralizing antibodies in multiple sclerosis patients treated with interferon beta 1-b. Neurology. 1999;52:1277–1279.

10 Panitch H, Goodin D, Francis G, et al. EVIDENCE (Evidence of Interferon Dose-response: European North American Comparative Efficacy) Study Group and the University of British Columbia MS/MRI Research Group. Benefits of high-dose, high-frequency interferon beta-1a in relapsing-remitting multiple sclerosis are sustained to 16 months: final comparative results of the EVIDENCE trial. J Neurol Sci. 2005;239:67–74.

11 Arnon R, Aharoni R. Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci U S A. 2004;101(Suppl 2):14593–14598.

12 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;45:1268–1276.

13 Ropper AG. Selective treatment of multiple sclerosis. N Engl J Med. 2006;354:965–967.

14 Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354:924–933.

15 Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–415.

16 Krishnan C, Kaplin A, Deshpande D, et al. Transverse myelitis: pathogenesis, diagnosis and treatment. Front Biosci. 2004;9:1483–1499.

17 Kennedy PG, Weir AI. Rapid recovery of acute transverse myelitis treated with steroids. Postgrad Med J. 1988;64:384–385.

18 Weinshenker BG. Plasma exchange for severe attacks of inflammatory demyelinating diseases of the central nervous system. J Clin Apher. 2001;16:39–42.

19 Balcer LJ, Galetta SL. Treatment of acute demyelinating optic neuritis. Semin Ophthalmol. 2002;17:4–10.

20 Visual function 5 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. The Optic Neuritis Study Group. Arch Ophthalmol. 1997;115:1545–1552.