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Clinical features of multiple sclerosis in adults
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Disclosures: Michael J Olek, DO Nothing to disclose. Francisco Gonzalez-Scarano, MD Employment: University of Texas Health Science Center, San Antonio; University of Pennsylvania. Equity Ownership/Stock Options: Multiple, but traded by advisors without my input [Pharmaceutical]. Other Financial Interests: NeuroLink [Venture Capital]. John F Dashe, MD, PhD Employee of UpToDate, Inc.

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Literature review current through: Jan 2015. | This topic last updated: Jul 16, 2014.

INTRODUCTION — Diseases that affect central nervous system myelin can be categorized as demyelinating (acquired, inflammatory) and dysmyelinating (abnormal formation of myelin, usually genetic basis) (table 1). The most common autoimmune inflammatory demyelinating disease of the central nervous system is multiple sclerosis (MS).

The clinical features and disease course of MS will be reviewed here. Other aspects of MS are discussed separately:

(See "Pathogenesis and epidemiology of multiple sclerosis".)

(See "Clinical course and classification of multiple sclerosis".)

(See "Clinically isolated syndromes suggestive of multiple sclerosis".)

(See "Diagnosis of multiple sclerosis in adults".)

(See "Symptom management of multiple sclerosis in adults".)

(See "Treatment of acute exacerbations of multiple sclerosis in adults".)

(See "Treatment of relapsing-remitting multiple sclerosis in adults".)

(See "Treatment of progressive multiple sclerosis in adults".)

PRESENTATION — Most patients with MS have relapsing-remitting disease, which typically presents in a young adult with a clinically isolated syndrome suggestive of MS such as optic neuritis, long tract symptoms/signs, a brainstem syndrome (eg, internuclear ophthalmoplegia), or a spinal cord syndrome (eg, transverse myelitis). Presenting symptoms and signs may be either monofocal (consistent with a single lesion) or multifocal (consistent with more than one lesion). A minority of adult patients have the primary progressive form of MS, which presents with gradual accumulation of disability from the onset, usually without superimposed acute relapses. The most common clinical presentation of primary progressive MS is a spinal cord syndrome with spastic paraparesis and no clear sensory level [1]. (See "Clinical course and classification of multiple sclerosis", section on 'Disease pattern' and "Clinically isolated syndromes suggestive of multiple sclerosis".)

A relapse is defined as the acute or subacute onset of clinical dysfunction typical of an acute inflammatory demyelinating event in the central nervous system, in the absence of fever or infection [2]. A relapse usually reaches its peak in days to several weeks, followed by a remission during which the symptoms and signs resolve to a variable extent. The minimum duration for a relapse has been arbitrarily established at 24 hours, though most are much longer. Clinical symptoms of shorter duration are less likely to represent new lesion formation or extension of previous lesion size.

Analysis of prospectively collected data from a cohort of 195 patients suggests that symptomatic demyelinating events in early relapsing-remitting MS have a tendency to recur in the same location (eg, spinal cord, optic nerve, brainstem) [3]. However, relapses can present with any of the typical clinical symptoms of MS, and there are no specific clinical features that can reliably distinguish the initial clinical attack of MS from a relapse, other than history. (See 'Clinical symptoms and signs' below.)

In the absence of a new demyelinating event, worsening of previous clinical dysfunction can occur in the setting of fever (see 'Heat sensitivity' below), physical activity, or metabolic upset, and may last for hours to a day or more. Such worsening is thought to reflect conduction block in previously demyelinated axons.

CLINICAL SYMPTOMS AND SIGNS — There are no clinical findings that are unique to MS, but some are highly characteristic of the disease (table 2). Common symptoms of MS (table 3) include sensory symptoms in the limbs or face, visual loss, acute or subacute motor weakness, diplopia, gait disturbance and balance problems, Lhermitte sign (electric shock-like sensations that run down the back and/or limbs upon flexion of the neck), vertigo, bladder problems, limb ataxia, acute transverse myelitis, and pain. The onset is often polysymptomatic.

Visual loss — Optic neuritis is the most common type of involvement of the visual pathways with MS (see "Optic neuritis: Pathophysiology, clinical features, and diagnosis"). It usually presents as acute or subacute unilateral eye pain that is accentuated by ocular movements [4]. This is followed by a variable degree of visual loss (scotoma) affecting mainly central vision. Bilateral simultaneous optic neuritis is rare in MS; its occurrence in isolation may suggest another diagnosis such as Leber hereditary optic atrophy, toxic optic neuropathy, or NMO spectrum disease. When bilateral optic neuritis occurs in patients with MS, the impairment begins asymmetrically and is usually more severe in one eye.

Physical examination of patients with optic neuritis reveals a relative afferent pupillary defect (Marcus-Gunn pupil). Disc edema may be observed on fundus examination when the acute optic neuritis lesion involves the head of the optic nerve, a finding more common in children than in adults. Most often the lesion of the optic nerve is retrobulbar, and fundus examination is normal in the acute stage. Later the optic disc becomes pale as a result of axonal loss and resultant gliosis. This pallor predominates in the temporal segment of the disc (temporal pallor).

Ninety percent of patients regain normal vision over a period of two to six months after an acute episode of optic neuritis. Desaturation of bright colors, particularly red, is often reported by recovered patients; some also report a mild nonspecific dimming. (See "Optic neuritis: Prognosis and treatment", section on 'Prognosis'.)

Bitemporal hemianopia is rare in MS and, if present, should raise the suspicion of a mass lesion compressing the visual pathways. Homonymous field defects are uncommon but can be seen in MS due to involvement of the optic radiations.

Internuclear ophthalmoplegia — Internuclear ophthalmoplegia (INO) refers to abnormal horizontal ocular movements with lost or delayed adduction and horizontal nystagmus of the abducting eye. It is caused by a lesion of the medial longitudinal fasciculus in the brainstem on the side of diminished adduction. Convergence is preserved. When present bilaterally, it is usually coupled with vertical nystagmus on upward gaze. A bilateral INO is most suggestive of MS but also can be observed with other intraaxial brainstem lesions, including brainstem glioma, vascular lesions, Arnold-Chiari malformations, and Wernicke encephalopathy. (See "Internuclear ophthalmoparesis".)

Sensory symptoms — Sensory symptoms are a common initial feature of MS (table 3) and are present in almost every patient at some time during the course of disease. The sensory features can reflect spinothalamic, posterior column, or dorsal root entry zone lesions. Symptoms are commonly described as numbness, tingling, pins-and-needles, tightness, coldness, or swelling of the limbs or trunk. Radicular pains also can be present, particularly in the low thoracic and abdominal regions. An intense itching sensation, especially in the cervical dermatomes and usually unilateral, is suggestive of MS.

The most common sensory abnormalities on clinical examination include:

Varying degrees of impairment of vibration and joint position sense

Decreased pain and light touch perception in a distal distribution in the four extremities

Patchy areas of reduced pain and light touch perception in the limbs and trunk

On testing sensation with a sharp object such as a pin, patients frequently report that the sharp feeling is increased, or feels like a mild electric shock, or that the stimulus spreads in a ripple fashion from the point at which it is applied. A bilateral sensory level is more common than a hemisensory (Brown-Séquard) syndrome.

Impairment of facial sensation, subjective or objective, is a relatively common finding in MS. Trigeminal neuralgia (see "Trigeminal neuralgia") in a young adult may be an early sign of MS. Facial myokymia, a fine undulating wave-like facial twitching, and hemifacial spasm also can be due to MS, but other causes of a focal brainstem lesion must be excluded. Unilateral facial paresis can occur, but taste sensation is almost never affected.

Lhermitte phenomenon — Lhermitte phenomenon is a transient sensory symptom described as an electric shock radiating down the spine or into the limbs most often after flexion of the neck [5]. It may be infrequent or occur with the least movement of the head or neck. Although most frequently encountered in MS, this symptom also can be seen with other lesions of the cervical cord, including tumors, cervical disc herniation, postradiation myelopathy, and following trauma. (See "Complications of peripheral nerve irradiation".)

Pain — Pain is a common symptom in patients with MS. A multicenter cross-sectional study assessed pain in 1672 patients with MS [6]. Overall, 43 percent of the patients reported one or more painful symptoms. Types of pain and their frequencies in this population were as follows:

Trigeminal neuralgia in 2 percent

Lhermitte sign in 9 percent

Dysesthetic pain in 18 percent

Back pain in 16 percent

Visceral pain in 3 percent

Painful tonic spasms in 11 percent

Vertigo — Vertigo is a reported symptom in 30 to 50 percent of patients with MS. It is commonly associated with symptoms reflecting dysfunction of adjacent cranial nerves such as hyper- or hypoacusis, facial numbness, and diplopia.

Nystagmus — Approximately 2 to 4 percent of patients with MS develop acquired pendular nystagmus [7,8]; most patients with this form of nystagmus have MS [9]. It is seldom a presenting sign of MS, more typically developing later in the course of disease and persisting indefinitely, resolving in only 5 percent. (See "Pendular nystagmus", section on 'Acquired pendular nystagmus'.)

Acquired pendular nystagmus is characterized by rapid, small-amplitude pendular oscillations of the eyes in the primary position resembling quivering jelly. Patients frequently complain of oscillopsia (subjective oscillation of objects in the field of vision), which impairs visual performance. Marked impairment of visual acuity may also be present, due in part to blurring from constant eye motion and perhaps also to concurrent optic neuropathy [8].

Motor symptoms — Paraparesis or paraplegia is more common than significant upper extremity weakness in patients with MS due to the frequent occurrence of lesions in the descending motor tracts of the spinal cord. Severe spasticity can occur, such that extensor spasms of the legs and sometimes the trunk may be provoked by active or passive attempts to rise from a bed or wheelchair.

Physical findings include spasticity, usually more marked in the legs than in the arms. The deep tendon reflexes are exaggerated, sustained clonus may be elicited, and extensor plantar responses are observed. All of these manifestations are commonly asymmetrical.

Occasionally, deep tendon reflexes are decreased due to lesions interrupting the reflex arc at a segmental level, and an inverted triceps reflex may be observed where the triceps contraction is lost and the efferent component is represented by a contraction of the biceps muscle. The Achilles reflex can be absent due to lesions of the sacral segments of the spinal cord, with or without concomitant sphincter and sexual problems. Occasionally, reduced reflexes reflect hypotonia resulting from cerebellar pathway lesions.

Amyotrophy can occur and is usually of the disuse type, most frequently affecting the small muscles of the hand. Less commonly, lesions of the motor root exit zones cause muscle denervation due to axon loss. Secondary entrapment neuropathies are also a cause of muscle atrophy in MS.

Incoordination — Gait imbalance, difficulty in performing coordinated actions with the arms, and slurred speech may occur as a result of impairment of cerebellar pathways. Physical examination typically reveals dysmetria, decomposition of complex movements, and hypotonia, most often observed in the upper extremities. An intention tremor may be noted in the limbs and in the head. Walking is impaired by truncal ataxia. Ocular findings of nystagmus, ocular dysmetria, and failure of fixation suppression (square wave jerks) suggest cerebellar or cerebello-vestibular connection dysfunction. Speech can be scanning or explosive in character. In severe cases there is complete astasia (inability to stand), inability to use the arms due to a violent intention tremor, and virtually incomprehensible speech. Cerebellar signs are usually mixed with pyramidal (corticospinal) tract signs.

Bowel/bladder/sexual function — Bowel, bladder, and sexual dysfunction are common in MS. The extent of sphincter and sexual dysfunction often parallels the degree of motor impairment in the lower extremities. The most common urinary complaint is urgency. Urinary incontinence becomes more common as the disease progresses, and an atonic dilated bladder that empties by overflow can be the end result. Other causes of urinary urgency and incontinence need to be considered in patients with MS (see "Approach to women with urinary incontinence"). Urinary tract infections are common in MS, particularly in women, and may increase the extent of bladder dysfunction.

Constipation is more common than fecal incontinence. These problems may be a result of both upper and lower motor neuron impairment in addition to decreased general mobility.

Sexual dysfunction is common in patients with MS. About 50 percent of patients become completely sexually inactive secondary to their disease, and an additional 20 percent become sexually less active. Men experience various degrees of erectile dysfunction. Most women preserve their orgasmic capabilities, sometimes even in the presence of complete loss of bladder and bowel function.

Sphincter and sexual dysfunction associated with MS are discussed in greater detail separately. (See "Symptom management of multiple sclerosis in adults", section on 'Sexual dysfunction' and "Symptom management of multiple sclerosis in adults", section on 'Sphincter dysfunction'.)

Heat sensitivity — Heat sensitivity (Uhthoff phenomenon) is a well-known occurrence in MS; small increases in the body temperature can temporarily worsen current or preexisting signs and symptoms [10]. This phenomenon is presumably the result of conduction block developing in central pathways as the body temperature increases [11]. Normally, the nerve conduction safety factor decreases with increasing temperature until a point is reached at which conduction block occurs; this point of conduction block is reached at a much lower temperature in demyelinated nerves.

Paroxysmal symptoms — Paroxysmal attacks of motor or sensory phenomena can occur with demyelinating lesions. Within the brainstem, lesions may cause paroxysmal diplopia, facial paresthesia, trigeminal neuralgia, ataxia, and dysarthria. Motor system involvement results in painful tonic contractions of muscles of one or two (homolateral) limbs, trunk, and occasionally the face, but these only rarely occur in all four limbs or the trunk. These paroxysmal attacks typically respond to low doses of carbamazepine and frequently remit after several weeks to months, usually without recurrence. These symptoms and their management are discussed in greater detail separately. (See "Symptom management of multiple sclerosis in adults", section on 'Paroxysmal symptoms'.)

Fatigue — Fatigue is a characteristic finding in MS, usually described as physical exhaustion that is unrelated to the amount of activity performed. Many patients complain of feeling exhausted on waking, even if they have slept soundly. Fatigue can also occur during the day but may be partially or completely relieved by rest. In addition, there appears to be a correlation between fatigue and disrupted sleep in MS patients. Fatigue is often seen in association with an acute attack and may precede the focal neurologic features of the attack and persist long after the attack has subsided. There is a poor correlation between fatigue and the overall severity of disease or with the presence of any particular symptom or sign. Fatigue associated with MS is discussed in greater detail separately. (See "Symptom management of multiple sclerosis in adults", section on 'Fatigue'.)

Depression — Affective disturbance occurs in up to two-thirds of patients with MS, and depression is the most common manifestation. Depression may be more common in patients with MS than in others with chronic medical conditions. It is not known whether depression in MS patients reflects a comorbid association with bipolar illness or an effect of frontal or subcortical white matter disease. Early trials suggested that treatment with interferon beta may contribute to the development of depression, but subsequent studies have not found such an association.

Euphoria is usually associated with moderate or severe mental impairment. Patients may also manifest a dysphoric state with swings from depression to elation. Mood disturbance in MS is discussed separately. (See "Symptom management of multiple sclerosis in adults", section on 'Fatigue'.)

Cognitive dysfunction — Frank dementia is an uncommon feature of MS, occurring in less than 5 percent of patients. It is usually only encountered in severely affected individuals. However, a significant percentage of patients with MS have cognitive impairment on the basis of neuropsychological testing, and cognitive impairment may be common even at the onset of MS. The most frequent abnormalities are with abstract conceptualization, recent memory, attention, and speed of information processing.

The degree of cognitive decline in patients with MS correlates with the severity of cerebral pathology on MRI, and cortical atrophy on MRI (image 1) correlates with cognitive impairment. Acute cerebral lesions occasionally manifest as a confusional state associated with progressive focal paralysis. Cognitive dysfunction in MS is discussed separately. (See "Symptom management of multiple sclerosis in adults", section on 'Cognitive dysfunction'.)

Epilepsy — Epilepsy is more common in patients with MS than in the general population, occurring in 2 to 3 percent of patients. Convulsions may be either tonic-clonic in nature or partial-complex. They generally are benign and transient and respond well to antiepileptic drug therapy or require no therapy, although up to 11 percent of patients with MS and epilepsy may develop intractable seizures. This issue is discussed in greater detail separately. (See "Symptom management of multiple sclerosis in adults", section on 'Seizures'.)

INVESTIGATIONS — The neuroimaging modality of choice for patients with MS is MRI; ancillary tests such as cerebrospinal fluid analysis are also useful (table 4). These are discussed in greater detail elsewhere. (See "Diagnosis of multiple sclerosis in adults".)

Magnetic resonance imaging — The characteristic MRI lesion is the cerebral or spinal plaque. Plaques suggestive of MS are typically found in the periventricular region, corpus callosum, centrum semiovale, and, to a lesser extent, deep white matter structures and basal ganglia (image 2 and image 3). MS plaques usually have an ovoid appearance, and lesions are arranged at right angles to the corpus callosum as if radiating from this area. The plaques appear hyperintense on proton density and T2-weighted studies.

Over 90 percent of patients with clinically definite MS have typical white matter lesions on MRI. On T1-weighted images, most MS lesions are isointense to white matter, but some are hypointense and appear as "black holes", particularly in the supratentorial region (image 2). These are thought by some authorities to represent areas of axonal loss. Gadolinium-enhancing lesions are sometimes observed on T1-weighted MRI and typically correspond to areas of high signal on T2-weighted and low signal intensity on unenhanced T1-weighted images. Gadolinium-enhancing lesions may correlate with active disease and acute inflammation in MS.

The MRI findings associated with MS are reviewed in detail separately. (See "Diagnosis of multiple sclerosis in adults", section on 'Magnetic resonance imaging'.)

Cerebrospinal fluid — In MS, the cerebrospinal fluid (CSF) has a normal appearance and the CSF pressure is normal. The total leukocyte count is normal in two-thirds of patients, exceeds 15 cells/µL in <5 percent, and only rarely exceeds 50 cells/µL. Oligoclonal bands (OCBs) are found in up to 95 percent of patients with clinically definite MS. (See "Diagnosis of multiple sclerosis in adults", section on 'Cerebrospinal fluid analysis'.)

DIAGNOSIS — Multiple sclerosis is a clinical diagnosis. The core requirement of the diagnosis is the demonstration of central nervous system lesion dissemination in time and space. The diagnosis of MS is discussed in detail elsewhere. (See "Diagnosis of multiple sclerosis in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient information: Multiple sclerosis in adults (The Basics)")


Most patients with MS have relapsing-remitting disease, which typically presents in a young adult with a clinically isolated syndrome suggestive of MS such as optic neuritis, long tract symptoms/signs, a brainstem syndrome (eg, internuclear ophthalmoplegia), or a spinal cord syndrome (eg, transverse myelitis). A minority of adult patients have the primary progressive form of MS, which presents with gradual accumulation of disability from the onset. (See 'Presentation' above.)

There are no clinical findings that are unique to MS, but some are highly characteristic of the disease (table 2). Common symptoms of MS (table 3) include sensory symptoms in limbs or face, visual loss, acute or subacute motor weakness, diplopia, gait disturbance and balance problems, Lhermitte sign (electric shock-like sensations that run down the back and/or limbs upon flexion of the neck), vertigo, bladder problems, limb ataxia, acute transverse myelopathy, and pain. The onset is often polysymptomatic. The typical patient presents as a young adult with two or more clinically distinct episodes of CNS dysfunction with at least partial resolution. (See 'Clinical symptoms and signs' above.)

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