Multiple Sclerosis: When to Suspect—Keys to Diagnosis

ABSTRACT: Multiple sclerosis (MS) is characterized by a typical clinical history of neurologic symptoms, separated in time and space, supported by laboratory tests. Key symptoms that signal MS—particularly in young adults—include unilateral vision loss, diplopia that lasts for days or weeks, and hemiparesis that has an insidious or slow onset. A Lhermitte sign can often be elicited, although this finding is not specific for MS. An MRI scan typically shows high-signal lesions on T2-weighted images in the periventricular white matter and often in the cerebellum and brainstem. The presence of oligoclonal bands in the cerebrospinal fluid is a useful but not essential finding to support the diagnosis of MS.

Key words: multiple sclerosis, optic neuritis
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Multiple sclerosis (MS) is the most common cause of disability among young adults. The neurologic symptoms of this progressive, debilitating disorder result from an autoimmune attack on the myelin that envelops the axons in the brain and spinal cord. Typical symptoms include unilateral visual loss (optic neuritis), diplopia that lasts for days or weeks, and hemiparesis that has an insidious or slow onset (Table 1).

The symptoms of MS wax and wane over time. As a result, unless the symptom affects function, such as gait, patients may not initially seek medical evaluation. Because most of the initial presenting symptoms resolve over brief periods (days to weeks), the diagnosis may be delayed for years (Box).

In this article, we describe common signs and symptoms of MS, as well as the laboratory findings that confirm the diagnosis. In an upcoming issue, we will discuss therapeutic options, especially treatments that are directed toward the underlying immunologic mechanisms of the disease.

EPIDEMIOLOGY

MS is more common in white than in black or Asian populations.¹ It is almost unknown in sub-Saharan Africa and is extremely rare in Japan. The disease is more common in higher latitudes in both the northern and the southern hemispheres. In general, MS is most common among persons of Scandinavian or Northern European descent. There are also geographic pockets of MS, the most notable being the Orkney Islands off the coast of Scotland.

Migration studies done in South Africa and Israel indicate that there may be a critical environmental exposure before the age of 15 years. The theory of an environmental trigger (ie, a virus) was supported by the discovery of an epidemic of MS in the Faroe Islands after British troops were stationed there in World War II.

MS is about 2 to 3 times as common among women as among men and usually begins in the 20s or 30s. Onset before age 10 and after age 60 is rare.

PATHOLOGY

The pathologic hallmark of MS is the plaque found in white matter tracts, and occasionally in gray matter, throughout the CNS. Acute plaque is characterized by perivenular cuffing by lymphocytes and macrophages with demyelination. Over time, astrocytes proliferate (gliosis), oligodendrocytes are lost, and further demyelination occurs. In addition, axons become transected in MS. This may be responsible for the permanent disability that the disease can produce.²

MS is a disease about "real estate": the location of the lesion is the primary factor in disability. For example, a single spinal cord lesion is more likely to be debilitating than multiple lesions in the subcortical white matter.

Postmortem studies indicate that MS is occasionally asymptomatic, and it has been suggested that asymptomatic MS may be at least as common as symptomatic disease.³

ETIOLOGY

MS is immunologically mediated.⁴ The combination of a genetic predisposition, an infectious agent, and an environmental trigger is the most widely accepted hypothesis for the origin of MS. Many viruses have been implicated; the most recent is the human herpesvirus 6 (HHV-6).⁵ This virus can cause a latent infection in the CNS. However, there is still no convincing evidence that a specific virus, such as HHV-6 or any other single virus, causes MS.⁴

CLINICAL COURSE

Patients with MS usually have one of the following clinical courses (Figure 1):

•Relapsing-remitting.
•Secondary progressive, with or without superimposed relapses.
•Primary progressive.

The relapsing-remitting course is the most common and carries the best prognosis. However, although symptoms remit, there is usually a mild residual deficit. Over time, these mild deficits produce disability.

After about 6 to 10 years, approximately 30% to 40%of cases of relapsing-remitting MS evolve into a progressive form (secondary progressive).⁶ In the progressive form, symptoms worsen insidiously without a clear period of remission. Relapses may be superimposed on a background of functional decline.

In the primary progressive form, there are no periods of remission. Instead, steady progression of symptoms leads to disability from the start. A rare, acute form of MS, often called Marburg syndrome, has an explosive course from the beginning and causes the rapid onset of disability and often death.

COMMON SYMPTOMS

Optic neuritis. Patients complain of vision loss, usually in one eye. Typically, it is heralded by pain in the involved eye, which is exacerbated by eye movement. Vision loss generally occurs over days to weeks.

If the demyelination involves the head of the optic nerve, papillitis or disc swelling can be observed on funduscopic examination. However, if the demyelination and swelling occur farther back on the course of the nerve (retrobulbar neuritis), the disc appears normal early in the course of disease. Color vision is particularly affected, and the patient will have difficulty in detecting bright red (dyschromatopsia). The patient usually exhibits an afferent pupillary defect (Marcus Gunn pupil), and after about a month, the optic disc may become pale.

Not every patient with optic neuritis has or will have MS; however, the occurrence of optic neuritis is highly predictive of having a second neurologic event and meeting the definition of clinically definite MS. In a patient who initially presents with optic neuritis, the overall likelihood that MS will develop is 30% over the next 5 years.⁷ MRI scanning at the time of presentation can be used to predict the risk of MS. If no lesions are detected with MRI, the risk is about 7%; if there are 3 or more lesions, the risk is about 90% at 10 years.⁸

Weakness in legs and spastic paraparesis. Most patients with MS will eventually have signs of myelopathy, including urinary incontinence, gait difficulty (often an ataxic or spastic paraparesis), and stiffness or spasticity of the legs. These symptoms may come on suddenly, as when there is a transverse myelitis, or develop more insidiously over the course of weeks.

In transverse myelitis, there is a rapidly evolving syndrome of leg and arm weakness, bladder involvement, and sensory loss accompanied by cerebrospinal fluid (CSF) changes, most notably a pleocytosis. Long-term follow-up studies of patients who present with an isolated episode of transverse myelitis indicate that clinically definite MS develops in 25% of those who have a normal brain MRI scan at diagnosis and that the disease progresses over 10 years in 67% of those with abnormal neuroimaging results.⁸

In some instances, transverse myelitis occurs shortly after an episode of optic neuritis. This combination is known as Devic syndrome. Devic syndrome appears to be distinct from MS.

Sensory complaints. A Lhermitte sign can often be elicited from patients with MS. This consists of an electric sensation traveling down the spine and often into the legs and arms when the patient flexes his or her neck forward. Although this symptom is not specific for MS, its presence in a young patient strongly suggests the disease.

Patients with MS often complain of constricting band-like paresthesias, which are thought to reflect small plaques in the spinal cord. These bands may be described as affecting the thorax, abdomen, arms, legs, or pelvis. If nothing is found on examination, the patient is often regarded as hysteric.

You may encounter other unusual sensory complaints from patients with MS. One of our patients presented with a distressing creeping-and-crawling sensation on her face that would come and go. On examination, she had a slight rippling of the muscles around her lip (facial myokymia).

Diplopia. Suspect MS when diplopia lasts for days to weeks in a young person. When you examine these patients, a common finding is an internuclear ophthalmoplegia (INO). When there is an INO, one eye cannot fully adduct, and abducting nystagmus on horizontal gaze develops in the other eye (Figure 2). An INO results from damage to the medial longitudinal fasciculus, a white matter tract, which traverses most of the brainstem.

Bilateral INO in a young person is virtually diagnostic of MS. A unilateral INO is often vascular in origin and is usually caused by a stroke in an elderly person. Always include MS and posterior circulation ischemia in the differential diagnosis of diplopia and vertigo in a young person.

Cognitive/behavioral problems. Many patients experience cognitive impairment or mood disorders or both. Common cognitive issues include difficulties in concentrating, easy distractibility, decreased verbal fluency, and psychomotor slowing. The development of cognitive problems may occur early or late in the disease process. Although it is somewhat unusual, some patients with MS may present with dementia.

The prevalence of depression is higher in patients with MS than in comparable patient populations. Unfortunately, depression is often unrecognized and consequently untreated. Several studies have found that more than one third of patients have a major depressive episode. In addition, two thirds of depressed MS patients were suicidal and had not received antidepressant medication; this emphasizes the need for identification of and intervention for depression in these patients.⁹

Incoordination. Ataxia is common in patients with MS. In some patients, truncal ataxia becomes so severe that they cannot sit up unassisted.

Speech. In many patients with MS, speechis also affected. So-called cerebellar speech is characterized as scanning or metered. The patient frequently puts the accent on the wrong syllable of the word. Dysphagia frequently accompanies dysarthria and should be screened for in order to avoid such complications as aspiration pneumonia.

Bladder incontinence. Urinary tract symptoms eventually develop in many patients with MS. Although the urinary symptoms usually take the form of urge incontinence, urinary retention may also occur. Urinary retention, although less common, may have more significant medical consequences, such as hydronephrosis and frequent urinary tract infections.

Hemiparesis. Although the vast majority of cases ofhemiparesis are caused by stroke, certain presentations should trigger a search for MS. In a young person, hemiparesis that has an insidious or slow onset with fluctuation suggests MS, especially if there has been a history of optic neuritis or other neurologic complaints.

Paroxysmal symptoms. Sudden and brief episodes of dysarthria, ataxia, and so-called spasms can occur in patients with MS. The spasms have been called tonic seizures, but this is a misnomer. These spasms consist of painful twisting of the extremities, often elicited by hyperventilation. It is thought that paroxysmal symptoms arise from areas of demyelination with cross talk between the neurons and axons.

Fatigue. One of the most disabling symptoms that patients complain about is fatigue. Fatigability makes employment difficult and is a primary reason why patients leave the workforce. In general, heat intensifies most symptoms of MS, including fatigue. Fatigue is not contingent on the level of disability, and it may be a prominent complaint in patients who have a normal neurologic examination.

Pain. This increasingly recognized complication of MS is reported in approximately 90% of patients. Common pain syndromes can be broadly divided into the following subtypes: paroxysmal, neurogenic, and musculoskeletal.

•The prototypical paroxysmal syndrome is trigeminal neuralgia. Trigeminal neuralgia, or tic douloureux, presents as severe lancinating, paroxysmal pain in the face. Trigeminal neuralgia that occurs in young adults, or bilaterally, raises suspicion for MS.
•Neurogenic pain has a characteristic numb, tingling, or burning sensation.
•Musculoskeletal pain may be primary or secondary, such as hemiparesis that leads to musculoskeletal pain in the compensating stronger side.

Spasticity. Increased tone in an extremity may be present at rest or appear during movement. Severe spasticity may interfere with hygiene or contribute to decubitus ulcer formation.

CONFIRMING THE DIAGNOSIS

MS is first and foremost a clinical diagnosis. In the past, MS was considered a diagnosis of exclusion; now, it is very much one of inclusion. MS is characterized by a typical clinical history of neurologic symptoms, separated in time and space, supported by laboratory tests. MRI and inspection of CSF are the most commonly used tests.

The diagnosis cannot be based solely on an MRI scan. There is no substitute for a careful history taking and neurologic examination. The clinical diagnosis relies on the following:

• At least 2 attacks in which 2 areas of the CNS were involved (eg, an episode of optic neuritis and an episode of weakness in the legs).
• Neurologic signs (such as optic pallor, spasticity in the legs, or cerebellar ataxia) that reflect at least 2 separate areas of CNS involvement.
• No disease that can better explain the signs and symptoms.

Table 2 lists some diseases commonly mistaken forMS.

MRI. The mainstay of laboratory confirmation is MRI of the brain; MRI of the cervical and thoracic spine may also be helpful. The MRI scan typically shows high-signal lesions on T2-weighted images in the periventricular white matter and often in the cerebellum and brainstem. These lesions are often clustered around the occipital horns of the lateral ventricles and staircase up the wall of the ventricle.

The importance of T1 black holes and atrophy has been increasingly recognized. Both T1 black hole formation and atrophy more closely correlate with the level of disability than do the classic T2 white matter lesions.¹⁰

Note that MRI findings are only supportive of a diagnosis of MS. The presence of enhancing lesions and nonenhancing lesions on a single scan, or a progression in the number of lesions on follow-up scans may help in meeting the diagnostic criterion of lesions disseminated in time. No MRI finding is pathognomonic of MS, but normal imaging results are unusual in patients with MS.

Lumbar puncture. The presence of oligoclonal bands in the CSF is also a useful—but not absolutely necessary—finding to support the diagnosis of MS. The CSF is examined for evidence of hyperactivity of the immune system. Oligoclonal banding refers to a restricted repertoire of IgG made by a few clones of plasma cells. In MS, these clones are found only in the CSF and not in the serum. For this reason, a serum specimen must be sent with the CSF specimen. Oligoclonal bands are found in many inflammatory diseases. Their presence is by no means specific for MS.

The rest of the CSF findings are generally unremarkable in patients who have MS. It is unusual to find a protein level of more than 100 mg/dL or a white blood cell count of more than 50/mL.

If we are fairly certain of the diagnosis of MS by the clinical picture, and if the MRI scan confirms the clinical impression, we usually do not perform a lumbar puncture for oligoclonal banding.