Clinically Isolated Syndromes
Neurologists frequently see patients who are having a first episode of neurologic symptoms and whose MRI scans show white-matter lesions. Many of the patients who experience these clinically isolated syndromes will go on to develop MS. Early treatment can delay a second episode in these patients.61,62 The argument in favor of early treatment is that some of the future relapses, and possibly some of the future disability, can be prevented. Arguments against early treatment are the uncertainty of the diagnosis early in the course, the limited effect of the available treatments, and the possibility of benign disease. The number of patients that are needed to be treated to prevent a single relapse of the disease varies with the number of T2 lesions found at presentation—a fact that helps guide the physician and patient in making a decision on early initiation of therapy.63
Progressive MS
Treatment of progressive MS is not as well established as it is for relapsing disease. As discussed [see Clinical Course, above],disease that is progressive from onset is called primary progressive, whereas disease that is initially characterized by relapses and remissions and then enters a progressive phase is called secondary progressive. Results of interferon-beta treatment in secondary progressive MS have been mixed and disappointing. In one trial of interferon beta-1b, disease progressed in 50% of the patients who received placebo, whereas disease progressed in 39% of patients treated with interferon beta-1b.64 However, subsequent studies of interferon beta-1a and beta-1b have not shown an effect on the progression of disability as measured by the Expanded Disability Status Scale (EDSS), the traditional measure of disability in MS.65,66 Relapse rates and MRI measures of disease activity were decreased in all of these studies. The available data suggest that glatiramer acetate likewise has limited or no benefit in either secondary or primary progressive dis-ease.67 Together, these results suggest that the pathophysiologic processes causing progressive symptoms may be different from those causing acute exacerbations and CNS inflammation detected by MRI.
In addition to interferon and glatiramer, various aggressive immunosuppressive therapies have been tried. The cytotoxic drug mitoxantrone has been approved for the treatment of aggressive relapsing and secondary progressive MS. In a 2-year, placebo-controlled study of 194 patients, 12 mg/m2 of mitox-antrone given every 3 months for 2 years reduced progression of disability, reduced relapse frequency by 67%, and decreased the accumulation of lesions and the number of enhancing lesions on MRI. In this study, the selection criteria were that the patients have active disease with recent deterioration and that they had not had previous therapy with interferon or glatiramer. Observed short-term side effects included nausea, hair loss, menstrual irregularities, and infections. The cumulative dose was limited because of the increasing risk of cardiotoxicity at higher doses.68
Mitoxantrone currently has a role for selected patients with very active disease, but its significant side effects limit its use. Several important questions about mitoxantrone remain to be answered. These include the duration of benefit, its effectiveness in patients with progressive disease without relapses, and its effectiveness in patients in whom interferon or glatiramer therapy has failed. Also of concern is the fact that numerous similar cyto-toxic or immunosuppressive agents were previously fashionable for a time but are currently little used because of limited benefit and significant side effects. These include cyclophosphamide, cladribine, azathioprine, methotrexate, and cyclosporine.
Symptomatic Therapy
Several of the common symptoms of MS respond to pharma-cologic treatment [see Table 4]. Prominent among the most frequent symptoms of MS are depression and fatigue.
Depression and fatigue Depression occurs in about 20% of MS patients, probably more frequently than anticipated for other chronic illnesses. Treatment of depression in MS patients does not differ from that in others. Fatigue is present in at least half of all MS patients; often, it is not proportional to the extent of neurologic compromise. It commonly occurs during relapses and can also be present between attacks. Fatigue in MS is differentiated from normal fatigue by its severity and by the fact that it is frequently unrelated to activity. About 50% of patients with MS obtain at least partial relief by treatment with amantadine, but dosing late in the day may induce insomnia and thus should be avoided. When amantadine fails to relieve fatigue, other agents that may be useful are modafanil,69,70 methylphenidate, and selective serotonin reuptake inhibitors.
Spasticity Spasticity is another common symptom that is amenable to treatment. The increased extensor tone in the lower extremities can to some extent compensate for associated weakness, but excessive spasticity inhibits a fluid gait and may result in painful spasms or joint contracture. Centrally active y-aminobutyric acid (GABA) agonists, such as baclofen, often reduce spasticity but preserve functional gait or lower-limb strength, which is needed for weight transfer. Effective doses of baclofen vary from as little as 5 mg to as much as 240 mg daily in divided doses. Treatment should be initiated at a low dose and titrated upward to the level that provides maximum benefit. Other drugs that may be helpful include diazepam, clon-azepam, and the alpha agonist tizanidine. Although not specifically investigated as an antispasmolytic agent, gabapentin may be useful in reducing spasticity. Some patients benefit from dantrolene. Selected patients who have severe spasticity that is unresponsive to oral treatment may benefit from intrathecal ba-clofen or selective botulinum toxin injections.
Bladder dysfunction Bladder dysfunction is common in MS. The pathophysiology is complex; the symptoms of detru-sor-sphincter dyssynergia, hyperactive detrusor function, and flaccid bladder may occur individually or in various combinations and often fluctuate over time. Formal urodynamic studies are essential to delineate these various patterns and to determine rational approaches to treatment. Most patients will present with urgency and frequency, which may be alleviated with smooth muscle relaxants and anticholinergic agents. Periodic determination of postvoid residual urine volumes is used to identify patients who will benefit from self-catheterization programs.
It is important to recognize that bladder infections are common in women with MS. Because of the frequent loss of perineal sensation, acute bladder infections may not cause dysuria but instead may become evident as a global deterioration of neurologic function, which may be mistaken for an acute relapse. The evaluation of patients in relapse should include a search for pyuria. Asymptomatic bacteriuria may demand concomitant treatment of acute relapses with a combination of methylpred-nisolone and an appropriate antibiotic. Significant urinary retention with overflow incontinence may be accompanied by reflex exaggeration of lower limb spasticity. Institution of a self-catheterization program for affected patients often reduces spas-ticity more effectively than pharmacotherapy.
Pain Pain is not uncommon in MS. Often, it is secondary to unusual mechanical stress resulting from asymmetrical weakness or spasticity. Appropriate orthotics, antispasmolytics, and self-performed exercise routines, supplemented by simple analgesics, are helpful. Paroxysmal pain syndromes, typified by trigeminal neuralgia, usually respond to low doses of carba-mazepine or other antiepileptic drugs, particularly gabapentin. Distal dysesthetic sensations may also respond to these drugs. Low doses of tricyclic antidepressants may prove useful.
Ataxia and intention tremor These manifestations are particularly difficult to manage. Use of counterweights on limbs may aid some patients. Pharmacologic interventions are generally disappointing, but clonazepam or gabapentin at maximally tolerated doses sometimes provides symptomatic relief for patients with disabling upper extremity ataxia.
Table 4 Symptomatic Therapy for MS*
|
Indication |
Drug |
Dosage |
|
Fatigue |
Amantadine |
100 mg b.i.d. or t.i.d. |
|
Methylphenidate |
10 mg b.i.d. to 20 mg t.i.d. |
|
|
Modafinil |
100 mg b.i.d. |
|
|
Bladder |
||
|
Urgency |
Oxybutynin |
5 mg b.i.d. to q.i.d. |
|
Tolterodine |
2 mg b.i.d. |
|
|
Imipramine |
25 to 75 mg q.h.s. |
|
|
Hyoscyamine |
0.125 mg b.i.d. to 0.25 mg q.i.d. |
|
|
Propantheline |
7.5 mg t.i.d. to 15 mg q.i.d. |
|
|
Dyssynergia |
Phenoxybenzamine |
10 mg b.i.d. to 20 mg t.i.d. |
|
Clonidine |
0.1 mg b.i.d. to 0.2 mg t.i.d. |
|
|
Terazosin |
1 to 5 mg q.d. |
|
|
Retention |
Intermittent catheterization |
Four or more times daily |
|
Bethanechol |
10 mg t.i.d. to 50 mg q.i.d. |
|
|
Spasticity |
Baclofen |
5 mg t.i.d. to 20 mg q.i.d. |
|
Diazepam |
2 mg t.i.d. to 10 mg q.i.d. |
|
|
Tizanidine |
4 mg q.d. to 12 mg t.i.d. |
|
|
Clonazepam |
0.5 mg t.i.d. to 5 mg q.i.d. |
|
|
Clonidine (adjunctive to baclofen) |
0.1 mg b.i.d. to 0.2 mg t.i.d. |
|
|
Dantrolene |
25 mg q.d. to 100 mg q.i.d. |
|
|
Ataxia |
Clonazepam |
0.5 mg t.i.d. to 5 mg q.i.d. |
|
Gabapentin |
100 to 600 mg t.i.d. |
|
|
Pain |
||
|
Paroxysmal |
Carbamazepine |
100 to 300 mg t.i.d. |
|
Phenytoin |
300 to 400 mg q.d. |
|
|
Misoprostol (trigeminal neuralgia) |
100 to 200 ^g q.i.d. |
|
|
Dysesthetic |
Amitriptyline |
50 to 150 mg q.h.s. |
|
Phenytoin |
300 to 400 mg q.d. |
|
|
Gabapentin |
100 to 600 mg t.i.d. |
|
|
Valproic acid |
250 to 1,000 mg t.i.d. |
*Usual adult doses for medications commonly used to treat MS syndromes. See appropriate reference for complete prescribing information, including contraindications, warnings, side effects, and initiation and termination of treatment.
Prognosis
Although the course of MS varies from patient to patient, the effect of the disease in large cohorts of MS patients has been determined. The median time from onset of disease to disability severe enough for the patient to require aids for ambulation is 15 years. MS has minimal effect on life span.20 For perhaps 10% to 15% of patients, MS has a relatively benign course, with patients experiencing minimal or no disability 20 years after onset of symptoms. For patients with relapsing-remitting disease, the mean relapse frequency is about once every 2 years. There are no known factors that are predictive of the clinical course in an individual patient, but female sex, younger age at onset, and optic neuritis or sensory symptoms as the presenting symptoms tend to be associated with a more favorable prognosis. A normal cerebral MRI in patients presenting with optic neuritis, partial transverse myelitis, and brain stem syndromes associated with MS predicts a mild course for the first decade or more of the disease.71
Optic Neuritis
Optic neuritis is an acute inflammatory optic neuropathy. The cardinal symptoms are unilateral vision loss and retrobul- bar pain with eye movement. MRI of the orbits is indicated to confirm the presence of optic nerve inflammation; brain MRI results are useful in counseling patients regarding their risk of developing MS. Referral to an ophthalmologist to exclude uveitis, glaucoma, or other ophthalmologic causes of visual loss is indicated. Differential diagnosis includes anterior ischemic optic neuropathy, which is usually painless and typically occurs in patients older than 50 years; hereditary diseases, such as Leber hereditary optic neuropathy; and toxic or nutritional optic neu-ropathies.72 Treatment with intravenous methylprednisolone at a dosage of 1 g/day for 3 days followed by oral prednisone for 11 days hastens recovery of vision but has little residual benefit at 1 year. One study showed that prednisone at 1 mg/kg/day for 14 days had no benefit and was associated with an excess of recurrences.73 Even without treatment, almost all patients begin to recover vision within 4 weeks.
The relation of optic neuritis to MS is controversial. Some regard optic neuritis as a distinct entity, but others consider it part of the clinical continuum of MS. More than half of all patients with MS have optic neuritis at some time during the disease. Of patients who present with optic neuritis and who have no other neurologic deficit, almost 40% have one or more ovoid or periventricular lesions visible on brain MRI; clinically definitive MS eventually develops in 60%.45,74 Patients with completely normal results on both MRI and comprehensive CSF evaluation seldom progress to MS.75
Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis (ADEM) is a mono-phasic syndrome that is usually preceded by a viral exanthem, an upper respiratory infection, or vaccination. The most commonly associated viruses are measles, paramyxovirus, varicella, rubella, and Epstein-Barr virus. Onset is often rapid and is characterized by meningeal signs, headache, seizures, and altered mental status. The associated neurologic deficits are variable and may include hemiplegia, paraplegia, sensory loss, vision loss, and transverse myelitis. ADEM can be fatal, but most patients begin to recover within 2 to 4 weeks.
Acute hemorrhagic encephalomyelitis is probably a fulminant variant of ADEM. The main pathologic features of ADEM are multiple areas of perivascular inflammation and demyelina-tion, without evidence of active viral infection. ADEM may be caused by an autoimmune response against myelin antigens elicited by cross-reactive viral proteins. Usually, multiple white-matter lesions are seen on MRI, and the majority of the lesions can be enhanced with contrast.76 Corticosteroid treatment is often used, although the efficacy of this approach has not been proved in clinical trials. Plasmapheresis may also be useful.77 Prognosis varies with the inciting virus, but in one case series, 89% of patients had good recovery.78
Transverse Myelitis
Acute transverse myelitis is a syndrome of spinal cord dys-function79; it has a rapid onset. Like ADEM, it may occur after infection or vaccination, or it may occur with no discernible precipitant. It may also be the initial presentation of MS. Symptoms include paraparesis, which is initially flaccid and then spastic; loss of sensation with a sensory level on the trunk; and bowel and bladder dysfunction. Back pain precedes the neurologic symptoms, and the sensory symptoms may begin distally and ascend. The thoracic cord is most often affected. 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 erythe-matosus. MRI is extremely useful for excluding structural lesions and for confirming the presence of an intramedullary lesion at the level in the spinal cord commensurate with the symptoms. The lesions of acute transverse myelitis 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. The lesions may cause swelling of the spinal cord.80,81 No treatment has proved beneficial, but corticosteroids are often used. Prognosis is variable: one third of patients have a good outcome, one third have a fair outcome, and one third do not recover.82 Spinal shock, back pain, and catastrophic onset are associated with poor outcome.
Inherited Demyelinating Diseases
Adrenoleukodystrophy
Adrenoleukodystrophy is an inherited disorder that is associated with progressive demyelination and dysfunction of the adrenal cortex.83 The inheritance pattern may be either autosomal recessive or X-linked recessive. The X-linked form is caused by the mutation of a gene encoding an integral membrane protein found in the peroxisome. Defects in this gene lead to accumulation of very long chain fatty acids (VLCFAs). The pheno-types may vary considerably, even within the same family. In the childhood form, the patient presents with cognitive deficits, and rapid neurologic deterioration ensues, with death occurring in 2 to 5 years. The adult form, called adrenomyeloneuropathy, presents in patients at a mean age of 28 years as progressive spinal cord dysfunction with spastic paraparesis, sensory loss, and bowel and bladder symptoms. Cerebral involvement may be minimal. Only half of patients with adult-onset disease have brain abnormalities on MRI; these are most often found in the corticospinal tracts.84 Most patients have diffuse atrophy of the spinal cord. Diagnosis is made on the basis of the combination of neurologic and adrenal involvement, family history, and elevated levels of serum VLCFAs. Dietary treatment with unsatu-rated fatty acids lowers the level of VLCFAs but does not significantly affect the progression of symptoms.85 Bone marrow transplantation may be effective if performed before severe symptoms develop. Prognosis is poor for patients with the childhood form of disease. Patients with adult-onset disease usually require assistance with ambulation within 10 to 15 years; in a large percentage of patients, rapidly progressive cerebral lesions develop 5 to 10 years after the onset of spinal cord symptoms.86
Metachromatic leukodystrophy
Metachromatic leukodystrophy is an autosomal recessive disorder that results in demyelination of axons in the central and peripheral nervous systems. It is caused by mutations in the gene for arylsulfatase A that lead to an accumulation of meta-chromatically staining sulfatides.87 Onset usually occurs in infancy or childhood; adult onset is rare. The symptoms of adult-onset disease are progressive behavioral abnormalities, dementia, ataxia, and neuropathy.88 MRI or CT of the brain demonstrates atrophy and diffuse white-matter abnormalities, particularly in the frontal lobes. Diagnosis is confirmed by measurement of arylsulfatase A activity in peripheral blood leukocytes, urine, or skin fibroblasts. True arylsulfatase deficiency must be distinguished from a common pseudodeficiency state that is caused by an allele with low enzymatic activity.87 The symptoms of metachromatic leukodystrophy are relentlessly progressive, and earlier onset is associated with more rapid progression. The mean survival for adult-onset disease is about 12 years. No effective treatment is available, but allogeneic bone marrow transplantation and gene therapy are under investigation.
Metabolic Demyelinating Diseases
Central pontine myelinolysis
Central pontine myelinolysis (CPM) is a syndrome in which neurologic deficits occur after rapid correction of hyponatremia [see 10:1 Renal Function and Disorders of Water and Sodium Balance].89 CPM usually occurs in young to middle-aged adults and is often associated with alcohol abuse or malnutrition. Signs and symptoms usually begin 3 days after the start of sodium replacement and consist of changes in mental status, dysarthria and other signs of corticobulbar dysfunction, and spastic quad-riplegia. Improvement usually begins about 2 weeks after the onset of symptoms, but the degree of recovery is variable. The most striking finding on pathologic examination is the presence of symmetrical demyelinated lesions in the central pons. De-myelinated lesions may also occur in a relatively symmetrical pattern in the basal ganglia, thalamus, internal capsule, subcorti-cal white matter, and cerebellum. T2-weighted MRI usually demonstrates the presence of hyperintense lesions. These lesions usually do not enhance with contrast. CPM may also occur after liver transplantation. There is no specific treatment once symptoms have developed. Long duration and rapid correction of hyponatremia increase the risk of CPM; the recommended rate for correction of hyponatremia is no faster than 10 to 12 mEq in 24 hours.
Vitamin b12 deficiency
Vitamin B12 deficiency results in demyelination of axons in the central and peripheral nervous systems. The dorsal and lateral white-matter tracts of the spinal cord are most affected—a characteristic that has given rise to the name subacute combined degeneration of the spinal cord. The most common presenting symptoms are paresthesias, sensory loss that begins in the feet and progresses proximally, and sensory ataxia.90 Weakness almost always begins after sensory loss. Memory difficulties, irritability, and confusion occur in a minority of patients. On examination, patients usually have decreased vibration and position sense, which is worse in the feet than in the hands, and they may have spastic paraparesis. Pathologic examination reveals symmetrical loss of myelin in the posterior and lateral columns of the spinal cord and sometimes patchy demyelination in the cerebral white matter. MRI of the spinal cord often demonstrates white-matter lesions, which resolve with treatment. Diagnosis is made on the basis of the clinical findings and a low serum cobalamin level. Macrocytosis or anemia is present in most patients but cannot be used in place of the cobalamin level as a diagnostic mea-sure.91 For patients who have symptoms and a low-normal coba-lamin level, demonstration of elevated levels of serum methyl-malonic acid and total homocysteine can confirm the presence of a functionally significant cobalamin deficiency.
If cobalamin deficiency is present, the underlying etiology should be investigated. About 80% of patients with cobalamin deficiency have pernicious anemia. Administration of cobalamin prevents progression of symptoms and produces clinical improvement in most patients [see 5:III Anemia:Production Defects].90 Nitrous oxide prevents the metabolism of cobalamin and can cause similar symptoms after prolonged exposure; after a single exposure, it can unmask a subclinical cobalamin deficiency.
Virus-Induced Demyelination
Progressive multifocal encephalopathy
Progressive multifocal encephalopathy is a lethal demyelinat-ing disease caused by an opportunistic viral infection of oligo-dendrocytes in immunocompromised patients. The causative agent is JC virus, a ubiquitous papovavirus that infects the majority of the population before adulthood and establishes a latent infection in the kidney. In immunocompromised hosts, the virus can reactivate and productively infect oligodendrocytes. This previously rare condition is now more common because it occurs in 4% of patients with AIDS. It appears to complicate natal-izumab treatment of both MS and Crohn disease. Patients usually present with relentlessly progressive focal neurologic deficits, such as hemiparesis or visual-field deficits, or with alterations in mental status. On brain MRI, one or more white-matter lesions are present; they are hyperintense on T2-weighted images and hypointense on T1-weighted images. There is no mass effect, and contrast enhancement is rare. Diagnosis can be confirmed by brain biopsy, with demonstration of virus by in situ hybridization or immunocytochemistry. Polymerase chain reaction amplification of JC virus sequences from the CSF can confirm diagnosis without the need for biopsy.92 Currently, there is no effective therapy. Survival after diagnosis is about 3 to 5 months in AIDS patients [see 11:XVII Central Nervous System Diseases Due to Slow Viruses and Prions].
Subacute sclerosing panencephalitis
Subacute sclerosing panencephalitis (SSPE) is a rare late complication of measles virus infection. It occurs most often in patients whose initial infection with measles virus occurred before 2 years of age; the mean lag time between initial infection and SSPE is 7 years. The use of measles vaccine has greatly reduced the incidence of this complication in developed countries. The earliest symptom is usually progressive cognitive deterioration, which is followed by motor dysfunction and myoclonus associated with distinctive electroencephalographic abnormalities. Pathologic examination reveals active viral infection in the brain, with measles virus protein and RNA detectable in both oligodendrocytes and neurons, and a vigorous inflammatory response. The course is progressive, with occasional temporary remissions. There is no satisfactory treatment [see 11:XVII Central Nervous System Diseases Due to Slow Viruses and Prions].
