Clinically isolated syndrome …

Elizabeth A Hartman MD

Neuroimmunology

Updated 06.27.2024
Released 06.07.2010
Expires For CME 06.27.2027

Clinically isolated syndrome

Author: Elizabeth A Hartman MD

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Editor: Anthony T Reder MD

Clinically isolated syndrome

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Introduction

Overview

A clinically isolated syndrome is a symptomatic episode of central nervous system dysfunction due to inflammatory demyelination. Risk factors for conversion to clinically definite multiple sclerosis have been identified, and treatment of high-risk individuals may delay subsequent relapses. Individuals with a clinically isolated syndrome may demonstrate accelerated brain atrophy and mild cognitive impairments. Revisions to the diagnostic criteria for relapsing-remitting multiple sclerosis are associated with a reduction in time to diagnosis of clinically definite multiple sclerosis in some patients presenting with an initial inflammatory event. In this article, the author summarizes the diagnosis, evaluation, and prognostic implications of radiologically and clinically isolated syndromes.

Key points

	• Clinically isolated syndromes such as optic neuritis, transverse myelitis, and other syndromes compatible with a first episode of CNS demyelination warrant prompt evaluation to determine underlying etiology.
	• Clinically isolated syndrome evaluation may yield important prognostic information regarding the risk of multiple sclerosis or may reveal an alternative diagnosis.
	• Early treatment of select clinically isolated syndrome patients may delay subsequent relapses and eventual conversion to clinically definite multiple sclerosis.
	• A “radiologically isolated syndrome” may have similar clinical significance to clinically isolated syndromes.

Historical note and terminology

The first journal article including the term “clinically isolated syndrome” appeared in 1993 (35). The increasing availability of MRI technology in the 1980s improved diagnosis of CNS demyelinating disorders, and the arrival of FDA-approved disease-modifying medications for multiple sclerosis starting in 1993 increased the importance of correct diagnosis and treatment. Long-term follow-up studies of patients presenting with an isolated clinical syndrome characteristic of multiple sclerosis led to the identification of baseline risk factors for conversion to clinically definite multiple sclerosis. Subsequent studies of clinically isolated syndrome patients revealed that early treatment with disease-modifying drugs might be beneficial in delaying a second demyelinating attack (48).

Other descriptions of clinically isolated syndromes include clinical onset of multiple sclerosis, isolated demyelination syndrome, first demyelinating episode, first presentation of multiple sclerosis, first attack of multiple sclerosis, and focal isolated idiopathic inflammatory demyelinating disorders.

The term “radiologically isolated syndrome” has evolved to describe individuals with brain MRI lesions suggestive of demyelination but without any associated clinical symptoms (30; 31).

Clinical manifestations

Presentation and course

	• Optic neuritis, partial transverse myelitis, brainstem syndromes, or long-tract sensory or motor syndromes are common clinically isolated syndrome presentations.
	• Clinically isolated syndrome symptoms develop in a subacute fashion. Without treatment, symptoms typically last about 6 weeks before spontaneous improvement with variable residual symptoms.
	• A patient with demyelinating changes noted on brain MRI without clinical symptoms or signs can be diagnosed with a radiologically isolated syndrome.

By definition, a clinically isolated syndrome develops in the absence of any prior history suggestive of demyelinating attacks and, thus, is the first or “isolated” symptom. Eight-five percent of patients with eventual multiple sclerosis diagnosis present with an initial clinically isolated syndrome (26). An attack (also called relapse or exacerbation) is defined as patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the CNS, lasting at least 24 hours in the absence of fever or infection (54). Specific symptoms vary based on the location of the inflammatory demyelinating lesion. Common clinically isolated syndromes include optic neuritis, partial transverse myelitis, brainstem syndromes, and long-tract sensory or motor syndromes. For example, the onset of unilateral blurred vision accompanied by pain with eye movements and a normal ophthalmologic examination suggests optic nerve demyelination (retrobulbar optic neuritis). Similarly, demyelination of the spinal cord may present with symptoms referable to the area of partial transverse myelitis. Depending on the level and fibers affected, a variable combination of sensory, motor or bladder and bowel dysfunction may be noted. Symptoms of CNS demyelination typically develop subacutely over hours or days and persist for days to weeks. Clinically isolated syndrome symptoms are indistinguishable from relapses (attacks) of relapsing-remitting multiple sclerosis. Patients typically recover over days to weeks with variable residual disability.

In 2008, a panel of multiple sclerosis experts recommended that a clinically isolated syndrome be defined as a monophasic presentation with suspected underlying inflammatory demyelinating disease and recommended five subtypes based on monofocal or multifocal symptoms, presence or absence of asymptomatic MRI lesions, or patients without symptoms but with a suggestive MRI (34). A clinically isolated syndrome is generally accepted to represent a first clinical event due to inflammatory demyelination of the central nervous system. Evaluation for other demyelinating etiologies is important (see Differential diagnosis below), and definitive multiple sclerosis diagnosis may require additional supportive features to demonstrate dissemination in time and space (54).

A preceding history of illness, vaccination, or trauma is occasionally noted and may indicate an alternative etiology or syndrome, such as postinfectious demyelination (including acute demyelinating encephalomyelitis) or postconcussive syndrome. Unusual presentations such as multifocal symptoms, complete or bilateral vision loss, complete paraplegia, or abrupt cognitive disturbances are not typical for multiple sclerosis relapses and should prompt evaluation for other etiologies, such as stroke, neuromyelitis optica spectrum disorder, or encephalitis.

Radiologically isolated syndrome describes an asymptomatic individual with brain MRI lesions consistent with demyelination (30; 31). Often, individuals undergo a brain MRI for research after an injury or other unrelated reason and incidentally are noted to have lesions that are consistent with demyelination. Demyelinating lesions are typically in periventricular, juxtacortical, infratentorial, or spinal cord locations; they are 5 mm or larger in size, often ovoid in shape, appear hyperintense on T2 or FLAIR, and may have associated T1 isointensity or hypointensity. Lesions must fulfill the 2005 multiple sclerosis criteria for dissemination in space by meeting three of the four features: (1) one gadolinium-enhancing lesion or nine T2-hyperintense lesions, (2) one or more infratentorial lesion, (3) one or more juxtacortical lesion, and (4) three or more periventricular lesions. Importantly, the lesions must not be related to any other medical explanation. Per the 2023 radiologically isolated syndrome criteria, if the prior criteria are not met, if the individual has one or two dissemination in space locations associated with two of the three following, then they meet criteria for radiologically isolated syndrome: spinal cord lesions, oligoclonal bands in the CSF, or dissemination in time on a follow-up MRI. The presence of the central vein sign and chronic active lesions with a paramagnetic rim may increase multiple sclerosis diagnostic criteria specificity, but this has not been validated (17).

Prognosis and complications

The risk of future demyelinating events and accumulation of disability are the main concerns after a clinically isolated syndrome. The risk of developing multiple sclerosis is estimated at 36% to 57% over a 2-year follow-up, depending on the diagnostic criteria applied (13). Patients with an abnormal baseline brain MRI (defined as one or more asymptomatic demyelinating lesions) have an 83% risk of developing clinically definite multiple sclerosis over the next 10 years (41). In patients with a clinically isolated syndrome, the updated 2017 McDonald criteria for multiple sclerosis shows a higher sensitivity, lower specificity, similar accuracy, and shorter time to multiple sclerosis diagnosis compared to the 2010 McDonald criteria (18). Changes in the multiple sclerosis diagnostic criteria over the last 25 years are associated with a decrease in time to multiple sclerosis diagnosis and treatment. Patients diagnosed in more recent diagnostic criteria periods have a lower risk of reaching disability (55). Factors that increase the risk of multiple sclerosis development include younger age, infratentorial or spinal cord lesions, and cerebrospinal fluid oligoclonal bands (02). Potential, though not yet definitive, risk factors may include smoking, vitamin D deficiency, Epstein-Barr virus infection, and HLA genes (33). In patients with a normal brain MRI, the risk of developing clinically definite multiple sclerosis is 23% for patients with oligoclonal bands in cerebrospinal fluid compared to 4% for patients without oligoclonal bands (56).

Long-term follow-up studies of predominantly untreated clinically isolated syndrome patients have shown that MRI lesions that are enhancing in the spinal cord or infratentorial are associated with an elevated risk of the eventual development of secondary progressive multiple sclerosis (07; 10).

For children and adolescents presenting with a clinically isolated syndrome, the risk of progression to multiple sclerosis over 5 years is 35%, and it is predicted by the presence of oligoclonal bands, prior Epstein-Barr virus infection, periventricular or corpus callosum lesions, or T1 hypointensity of lesions (44). Individuals with pediatric demyelinating syndrome warrant close follow-up due to 30% risk of progression via new symptoms or an MRI change within the first year (09). In multiple sclerosis patients, a median time from onset to Expanded Disability Status Score of 6 (use of an assistive device for ambulation) ranges from 15 to 20 years after diagnosis, and 50% to 80% of predominantly untreated patients eventually develop secondary progressive multiple sclerosis (12). In a 30-year follow-up cohort of clinically isolated syndrome patients, a higher burden of cortical lesions and lower gray matter volume were associated with a secondary progressive rather than relapsing-remitting multiple sclerosis course (21).

Progression of disability independent of relapses was observed in 27.6%, and relapse-associated disability worsening was noted in 17.8% of prospectively followed clinically isolated syndrome or early multiple sclerosis patients (46). Longer exposure to disease-modifying therapy was associated with a lower risk of progression independent of relapse activity and relapse-associated worsening. Early treatment of clinically isolated syndrome patients with disease-modifying drugs delays second relapse in high-risk patients, and halting early disease activity may reduce the risk of future disability progression (48). A multicenter study revealed an adjusted hazard ratio of 6.3 for confirmed disability progression in untreated compared to treated patients with clinically isolated syndrome (03), and a retrospective review of a large prospectively studied cohort of clinically isolated syndrome patients showed that early treatment improves prognosis (55). Natural history studies reveal a strong correlation between the number of relapses in the first 2 years of disease and time to future disability (50). Thus, early control of disease activity may have a benefit in terms of disability accumulation. There is evidence of early brain atrophy and poor cognition, even within the first year after a clinically isolated syndrome, which adds to the urgency of correct diagnosis and potential treatment (45).

Some individuals with a radiologically isolated syndrome eventually develop clinically definite multiple sclerosis. Overall, 51% of individuals with radiologically isolated syndrome convert to multiple sclerosis. Factors that increase the risk of multiple sclerosis development include younger age, infratentorial or spinal cord lesions, and cerebrospinal fluid oligoclonal bands. The risk of developing multiple sclerosis for individuals with all four risk factors is 87% (29).

Clinical vignette

A 36-year-old man with a history of controlled hypertension developed right retro-orbital discomfort associated with mild blurred vision “as if looking through a film” and with worsening over the next 2 days to an inability to read with the right eye. Ophthalmology evaluation did not reveal any ocular abnormalities, and he was started on high-dose oral steroids (prednisone 1250 mg orally, daily for 3 days) and referred to Neurology for further workup. No other prior neurologic events or abnormal symptoms were reported. A right afferent pupillary defect was noted as well as red desaturation with visual acuity of 20/80 with otherwise normal detailed neurologic examination. Brain and orbit MRI with and without contrast revealed post-contrast enhancement of the right optic nerve with slight T2 hyperintensity and a nonenhancing single, rounded 4 mm subcortical left frontal white matter hyperintensity. A cervical spine MRI revealed normal cord signal throughout. Laboratory testing was negative for NMO and MOG antibodies in serum, with normal B12, ESR, Lyme screen, and ANA. The patient deferred cerebrospinal fluid testing.

The patient was diagnosed with clinically isolated syndrome based on the demyelinating event of optic neuritis and lack of dissemination in time or space per the 2017 McDonald criteria. After discussing the risk of developing multiple sclerosis and the risks and benefits of disease-modifying therapy, serial brain MRIs were recommended at the initial 6-month interval, followed by annually for 5 years or sooner if the patient noted new symptoms. The patient’s vision improved to 20/30 at the 6-month follow-up, with mild increased blurred vision noted by the patient when exercising and with a stable brain MRI. A new, nonenhancing periventricular T2 hyperintensity and an enhancing cerebellar lesion were noted on the 12-month follow-up brain MRI. After discussion, the patient was started on disease-modifying therapy for relapsing-remitting multiple sclerosis.

Biological basis

Etiology and pathogenesis

	• Environmental triggers may lead to the development of a clinically isolated syndrome in a genetically susceptive individual.
	• Demyelinating events, including a clinically isolated syndrome, are associated with prior Epstein-Barr virus exposure, low vitamin D levels, tobacco use, and obesity.

The cause of a clinically isolated syndrome may be idiopathic. Not all patients subsequently develop multiple sclerosis, and other etiologies of demyelination must be considered (see differential diagnosis). In idiopathic cases, both genetic and environmental factors are believed to play a role. Please see the Medlink article on multiple sclerosis for a detailed review.

The pathogenesis and pathophysiology of a clinically isolated syndrome variy by the underlying etiology of the demyelinating event. Low vitamin D levels and increased immunoreactivity to Epstein-Barr virus compared to controls have been detected in patients before clinically isolated syndrome onset (14). Childhood and adolescent obesity is associated with increased susceptibility to multiple sclerosis (20). Clinically isolated syndromes may reflect self-limited disorders or chronic, inflammatory conditions. An understanding of what distinguishes these self-limited forms of demyelination from chronic conditions is lacking. Postinfectious demyelinating events may remain isolated or herald the onset of multiple sclerosis. Monophasic clinically isolated syndromes may be seen with the use of tumor necrosis factor inhibitor therapy in autoimmune diseases, though differentiating between demyelination due to drug effect and the underlying condition may be difficult (22). An improved understanding of the underlying pathogenesis of isolated versus chronic relapsing or progressive demyelinating events may lead to improved knowledge of underlying risk factors and therapeutic options.

Chronic cerebrospinal venous insufficiency syndrome (CCSVI) has been postulated as a cause of multiple sclerosis. However, a study revealed the presence of CCSVI criteria in only 38.1% of clinically isolated syndrome patients, 56.1% of multiple sclerosis patients, and 22.7% of healthy controls and, thus, argues against CCSVI as the etiology of demyelinating disease (61). Further, a randomized prospective trial with venous angioplasty failed to show any benefit (52).

Prevention

	• Avoidance of childhood obesity and cigarette smoke exposure may reduce the risk of developing a demyelinating event such as a clinically isolated syndrome.
	• Vaccination is a promising way to reduce the risk of infectious or parainfectious demyelinating events.

Given the heterogeneous etiologies and often idiopathic nature of clinically isolated syndromes, no clear means of prevention exists. In patients with postinfectious clinically isolated syndrome, preventing the inciting infection is an attractive means of prevention. In acute disseminated encephalomyelitis, approximately 70% of cases are associated with an infection, and approximately 5% with vaccination (05). Acute disseminated encephalomyelitis rates are estimated at one to two per million in association with the live measles vaccine compared to one in 1000 risk of postinfectious acute disseminated encephalomyelitis with measles infection, supporting that vaccination may decrease the risk of postinfectious acute demyelinating complications. However, vaccinations do not exist for all viral or bacterial agents.

Risk factors for multiple sclerosis include Northern European ancestry, decreased sun (ultraviolet) exposure, tobacco smoking, vitamin D deficiency, geographic location farther from the equator, Epstein-Barr virus infection, genetic factors, female gender, and childhood obesity (28; 20). Abstinence or discontinuation of tobacco use may reduce the risk of developing multiple sclerosis. A prospective study revealed that smoking at the time of clinically isolated syndrome diagnosis was an independent risk factor for conversion to clinically definite multiple sclerosis, with a hazard ratio of 2.3 (58). A double-blinded randomized trial of vitamin D3 treatment in high-risk clinically isolated syndrome patients did not show benefits compared to placebo for three different vitamin D supplementation doses (08). Pregnancy does not appear to increase the risk of a clinically isolated syndrome and is associated with later onset of clinically isolated syndrome compared to women with no prior pregnancy, with a median delay of 3.3 years (38).

Differential diagnosis

Confusing conditions

A clinically isolated syndrome implies that a patient has a clinical symptom present. This differs from a radiologically isolated syndrome, where demyelinating lesions are found without associated symptoms. Many cases of radiologically isolated syndrome may be found incidentally, such as when an individual undergoes brain MRI for headache, research purposes, or pituitary evaluation.

Associated or underlying disorders

• Optic neuritis
• Transverse myelitis
• Internuclear ophthalmoplegia
• Central nervous system demyelination

The differential diagnosis for clinically isolated syndromes is broad but can be grouped into idiopathic inflammatory demyelinating disorders, autoimmune disorders, infectious or postinfectious processes, malignancy, vascular conditions, nutritional/metabolic disorders, genetic disorders, or others.

Idiopathic inflammatory demyelinating disorders. Multiple sclerosis is the most common idiopathic, inflammatory demyelinating disorder of the CNS. Multiple sclerosis is a chronic, inflammatory neurodegenerative disease with varying clinical presentations, including relapsing-remitting, secondary progressive, relapsing-progressive, and primary progressive forms. Relapsing-remitting is the most common (85%) form of multiple sclerosis and is characterized by relapses of neurologic dysfunction over time affecting different parts of the CNS. After 10 years or more, relapsing-remitting multiple sclerosis commonly transitions to secondary-progressive multiple sclerosis. Secondary progressive multiple sclerosis is characterized by slowly worsening disability, often in the absence of clear relapses. Primary progressive multiple sclerosis tends to affect older individuals with an equal male-to-female incidence and typically does not have attacks. The conversion rate from a clinically isolated syndrome to clinically definite multiple sclerosis varies from 56% to 82% in prospective studies (04; 16).

Neuromyelitis optica spectrum disorder (NMOSD) or Devic disease commonly presents with optic neuritis or transverse myelitis. Many neuromyelitis optica spectrum disorder patients do not have demyelinating lesions noted in the brain, unlike multiple sclerosis patients, though when demyelinating lesions are present, they are more commonly noted in the brainstem near the fourth ventricle and with features that are not typical for multiple sclerosis demyelinating lesions. Relapsing neuromyelitis optica presents with recurrent, often severe, bouts of optic neuritis or longitudinally extensive transverse myelitis. Neuromyelitis optica may also be a monosymptomatic disorder and has been noted in association with autoimmune disorders such as lupus or Sjögren syndrome. Neuromyelitis optica spectrum disorder criteria define diagnosis in the presence of positive neuromyelitis optica IgG antibody and either optic neuritis or transverse myelitis. If neuromyelitis optica IgG antibody is absent, then a core clinical characteristic of optic neuritis, acute myelitis, or area postrema syndrome is required as well as dissemination in space and specific MRI criteria (23). A subset of nearly one third of individuals suspected to have NMO IgG antibody negative neuromyelitis spectrum disorder have been found to have antimyelin oligodendrocyte glycoprotein (MOG) antibodies. Anti-MOG demyelinating disorders tend to manifest as bilateral optic neuritis, combined optic neuritis and myelitis, or brainstem encephalitis at times with seizures with anti-MOG antibody positive in serum and not in the cerebrospinal fluid (60). Cerebrospinal fluid oligoclonal bands are typically negative in anti-MOG disease.

Autoimmune disorders. Autoimmune disorders such as systemic lupus erythematosus, Sjögren syndrome, and antiphospholipid antibody syndrome may also present with focal CNS symptoms and demyelinating lesions (53). Differentiating factors include associated rheumatic symptoms, including arthralgias, dermatologic changes, and the presence of autoantibodies in serum. Of note, increased incidence of positive antinuclear antibodies have been noted in multiple sclerosis patients compared to the general population, but are usually of a titer less than 1:160. Autoantibodies can be found in 29% of clinically isolated syndrome patients, though only 1.8% have an associated underlying autoimmune disease (37).

Sarcoidosis is a granulomatous disorder confirmed by the presence of noncaseating granulomas in tissue biopsy and the absence of fungal, tuberculosis, or other infectious process. Cranial neuropathies, hypothalamic-pituitary dysfunction, and optic neuritis are common CNS manifestations of neurosarcoidosis, which may occur in 5% to 10% of patients with systemic sarcoidosis. MRI may reveal leptomeningeal enhancement and lesions that may mimic demyelination or tumors.

Behçet disease may rarely present with neurologic symptoms and abnormal brain MRI. Symptoms to suggest Behçet disease include oral or genital ulcers, characteristic skin and eye findings, gastrointestinal symptoms, arthralgias, and vascular complications (01).

Tumor necrosis factor inhibitors used in rheumatoid arthritis, Crohn disease, or psoriasis may be associated with demyelination and neurologic symptoms. Patients with a family history of multiple sclerosis may be at increased risk for demyelination associated with tumor necrosis factor inhibitors.

Infectious and postinfectious disorders. Infections such as human T-cell lymphotropic virus-1 (tropical spastic paraparesis), tuberculosis, HIV, syphilis, hepatitis, Bartonella henselae, neuroborreliosis, SARS-CoV-2, and others may result in focal neurologic symptoms that may be associated with infectious of parainfectious complications, which initially mimic a clinically isolated syndrome. Progressive multifocal leukoencephalopathy is an infectious demyelinating disorder caused by the JC virus and occurs more often in immunocompromised individuals, though it is also seen in association with the use of some multiple sclerosis disease-modifying therapies. Fever or other signs of infection may be noted in infectious demyelinating syndromes, and appropriate blood cultures or cerebrospinal fluid testing is indicated when clinical suspicion arises. Without treatment of the underlying infection, progression is typical in these disorders.

Acute disseminated encephalomyelitis typically occurs in children and young adults within 6 weeks of antecedent illness or vaccination and is associated with encephalopathy and varied, often multifocal, CNS symptoms. Imaging reveals often large, confluent, ill-defined lesions sparing the periventricular regions and may include grey matter lesions. A history of fever, upper or lower respiratory symptoms, or diarrheal illness several days before the onset of symptoms suggests a postinfectious etiology. A specific infectious trigger is rarely identified, but includes a variety of common viruses.

Optic neuritis, multiple sclerosis, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO) spectrum disorder, and myelin oligodendrocyte glycoprotein (MOG) antibody associated disease have been noted in association with SARS-CoV-2 infection, also referred to as COVID-19 illness (15).

Neoplasm. Benign or malignant neoplasms may occasionally mimic demyelinating symptoms, but can often be distinguished by imaging features. In addition, tumefactive (brain lesion larger than two centimeters) presentations of demyelinating disorders occur. If imaging features, spinal fluid results, and a therapeutic trial of steroids fail to distinguish the etiology, a brain biopsy may be required to distinguish demyelination from malignancy. Paraneoplastic syndromes such as cerebellar degeneration associated with presence of anti-Yo (Purkinje cell cytoplasmic or PCA type 1) antibody may also be initially confused with a demyelinating disorder, but can be distinguished by progressive clinical course and presence of serum or cerebrospinal fluid paraneoplastic antibodies.

Vascular. Cerebrovascular events such as ischemic or hemorrhagic strokes present with acute onset symptoms and can be differentiated by MRI features, including diffusion-weighted imaging and vascular territory involvement. Fabry disease is a genetic disorder that may present with ischemic strokes and may mimic a relapsing-remitting pattern suggestive of multiple sclerosis. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is another genetic cause of stroke that may mimic demyelinating disorders. Susac syndrome, or retinocochleocerebral vasculopathy, is associated with the triad of encephalopathy, retinal artery occlusion, and hearing loss, and brain MRI reveals white matter lesions with corpus callosum involvement. Illicit drugs of abuse such as methamphetamines, cocaine, heroin, and cannabis may cause MRI changes, including nonspecific white matter hyperintensities that may reflect ischemic strokes due to drug-induced vasospasm or arteritis.

Nutritional/metabolic. Vitamin deficiencies, including vitamin B12 deficiency, copper myelopathy, folate deficiency, and vitamin E deficiency, may present with focal neurologic symptoms but generally have a more subacute onset. Central pontine myelinolysis is a syndrome of noninflammatory demyelination that typically develops after rapid correction of hyponatremia, leading to osmotic demyelination. Imaging reveals characteristic involvement of the pons, though extrapontine involvement has also been noted. Marchiafava-Bignami disease is characterized by demyelination of the corpus callosum and may present with mental status changes, seizures, and weakness. It is more commonly noted in male alcoholics.

Genetic. Hereditary leukodystrophies lead to demyelination but typically present with progressive symptoms. In addition, brain MRI often reveals diffuse, confluent demyelination rather than discrete lesions. Hereditary demyelinating disorders often present in childhood, but adult forms exist including adrenoleukodystrophy or adrenomyeloneuropathy, metachromatic leukodystrophy, Alexander disease, Canavan disease, cerebrotendinous xanthomatosis, Refsum disease, Pelizaeus-Merzbacher disease, and globoid cell leukodystrophy. Characteristic MRI features may help guide diagnostic evaluation of suspected genetic leukodystrophies (51). Leber hereditary optic neuropathy is a mitochondrial disorder that leads to acute or subacute loss of central vision due to degeneration of retinal ganglion cells. Especially in women, Leber hereditary optic neuropathy may have a multiple sclerosis-like presentation (24).

Diagnostic workup

• Detailed history to screen for prior events, careful neurologic examination, neuroimaging with brain or spine MRIs (both pre- and post-contrast), and laboratory testing to exclude alternative causes is vital in the evaluation of every clinically isolated syndrome patient.

Evaluation of a patient with clinically isolated syndrome must include a detailed history, examination, lab, and neuroimaging. A thorough history of symptoms will distinguish those that are compatible with a demyelinating attack from migraine, seizure, stroke, or other neurologic disorder. It is also important to inquire about prior neurologic symptoms that could represent a preceding relapse. A detailed neurologic examination is performed to evaluate for objective findings consistent with central nervous system dysfunction, such as an afferent pupillary defect and color desaturation in the affected optic neuritis eye, or sensory level and reflex changes in partial transverse myelitis. Laboratory screening with vitamin B12, C-reactive protein, and antinuclear antibody is commonly performed, with additional testing to exclude alternative etiologies based on patient risk factors and history, such as angiotensin-converting enzyme, NMO-IgG and/or MOG antibodies, extractable nuclear antigen panel, rapid plasma reagin, Lyme antibodies or western blot, or others. MRI interpretation should be done with extra caution in patients with migraine with aura or multiple vascular risk factors to avoid overdiagnosis. A threshold of three periventricular lesions is more specific for clinically isolated syndrome in patients with migraine with aura (27).

Multiple sclerosis is a clinical diagnosis based on typical symptoms, examination findings, characteristic neuroimaging results, and ancillary tests as indicated, as well as ruling out alternative explanations. Hallmarks of multiple sclerosis diagnosis include dissemination in space (DIS), which refers to multiple, separate areas of central nervous system involvement, and dissemination in time (DIT), which refers to attacks of inflammation occurring over a minimum of 1 month’s time between episodes. Per the 2017 McDonald Criteria, relapsing-remitting multiple sclerosis can be diagnosed when both dissemination in space and dissemination in time criteria are met. Dissemination in space may be met when one or more symptomatic or asymptomatic lesions are noted in at least two characteristic locations (periventricular, juxtacortial or cortical, infratentorial, or spinal cord). Dissemination in time is met when two more historical attacks can be confirmed by clinical examination, or at least one historical attack is confirmed by clinical examination, and at least one different historical attack is confirmed by a lesion on neuroimaging in a region that would cause the historical symptoms. In those with a single attack, dissemination of time may be met if there is a future clinical attack, presence of both enhancing and nonenhancing lesions, typical multiple sclerosis lesions on MRI, if a new T2 or enhancing multiple sclerosis typical lesion is noted compared to baseline MRI, or if oligoclonal bands are present in cerebrospinal fluid (and not in serum). In patients presenting with at least 1 year of progressive symptoms from onset, primary progressive multiple sclerosis can be confirmed if at least two of the following criteria are met: one or more symptomatic or asymptomatic lesion(s) in periventricular, juxtacortial or cortical, infratentorial, or spinal cord location(s), two or more spinal cord lesions, or presence of cerebrospinal fluid specific oligoclonal bands. It is important to remember that these criteria were developed based on patients presenting with typical demyelinating symptoms (which may include a clinically isolated syndrome), and, therefore, further evaluations may be indicated to rule out alternative etiologies if atypical or nonspecific symptoms are present, and in individuals with comorbid conditions such as migraine or vascular risk factors with nonspecific MRI lesions.

Neuroimaging is part of a standard evaluation for demyelinating disorders. MRI is more sensitive (90% to 97%) for multiple sclerosis than CT imaging (approximately 33%), though CT may be performed in patients with a contraindication to MRI. Abnormal T2 lesions are noted in 50% to 70% of individuals with a clinically isolated syndrome (39). Clinically isolated syndrome patients with lesions on baseline brain MRI have an approximately 80% chance of developing multiple sclerosis in 10 years (41). In converse, patients with no brain MRI lesions have a less than 20% chance of developing multiple sclerosis. Demyelinating lesions appear bright or hyperintense on T2 and FLAIR sequences, isointense or hypointense on T1 imaging, and when acute (less than six weeks) may have associated open-ring or C-shaped peripheral gadolinium enhancement. Diffusion-weighted imaging may be positive in acute lesions, but apparent diffusion coefficient sequences will also appear bright, reflecting T2 “shine through” rather than impaired diffusivity as noted with acute ischemic processes. Demyelinating lesions of the white matter are noted more easily than gray matter lesions on conventional MRI, though both are present in multiple sclerosis. Typical locations of white matter demyelinating lesions include periventricular, especially perpendicular to the ventricles (Dawson fingers) and adjacent to or involving the corpus callosum, juxtacortical, infratentorial, and spinal cord.

When there is diagnostic or prognostic uncertainty, lumbar puncture for cerebrospinal fluid analysis may be useful. An elevated white blood cell count (over 100) suggests infection, though a mild lymphocytic pleocytosis may be noted in noninfectious inflammatory disorders such as multiple sclerosis. The presence of increased immunoglobulin G index or synthesis rate is a sign of intrathecal antibody response and is more suggestive of multiple sclerosis. The presence of cerebrospinal fluid-specific oligoclonal bands in clinically isolated syndrome patients demonstrated 88% sensitivity and 43% specificity for multiple sclerosis, as well as 88% negative predictive value (56). Oligoclonal bands may also be present in systemic lupus erythematous, Sjögren syndrome, neurosarcoidosis, neurosyphilis, paraneoplastic disorders, acute inflammatory demyelinating polyradiculoneuropathy, subacute sclerosing panencephalitis, adrenoleukodystrophy, tropical spastic paraparesis, and chronic meningitis.

Electrophysiologic testing including visual evoked potentials (80% to 85% sensitive), somatosensory evoked potentials (75% sensitive), or brainstem auditory evoked potentials (65% sensitive) may also be used to evaluate for subclinical deficits in neuronal transmission suggestive of underlying central nervous system demyelination.

A biopsy is not a prerequisite for diagnosing demyelinating disorders and is only considered in cases of significant diagnostic uncertainty and to rule out malignancy.

A cerebral angiogram may be considered in cases where vasculitis, vasospasm, intracranial stenosis, or vascular malformation is suspected but is not typically performed when evaluating clinically isolated syndrome.

Management

	• Low-risk clinically isolated syndromes may be followed with serial neuroimaging.
	• Disease modifying treatment of high risk clinically isolated syndrome patients reduces the risk of new relapse, new MRI lesions, and risk of conversion to multiple sclerosis.

Observation and serial monitoring are typically recommended in individuals with a low risk of clinically isolated syndrome or radiographically isolated syndrome or in those with atypical features. Clinical follow up and serial MRIs at an initial 3- to 6-month interval, followed by 6- to 12-month intervals, are typically performed over the first 5 years after presentation. Acute treatment of symptomatic, debilitating demyelinating events includes high-dose corticosteroids to speed the rate of neurologic recovery. Steroids are typically given intravenously in a dose of 1000 mg of methylprednisolone or an equivalent oral prednisone dose of 1250 mg daily for 3 to 7 days (36). High-dose steroid treatment may be followed by a brief oral steroid (often prednisone) taper, though there are no data to support the benefit of steroid tapers. Patients with severe attacks and incomplete recovery after steroids may be treated with a second course of steroids or with plasmapheresis (06). Fulminant initial demyelinating attacks are sometimes treated with cyclophosphamide or other investigational chemotherapeutic agents, but controlled studies of short-term and long-term efficacy are lacking.

Once other etiologies have been excluded, if a patient presenting with a clinically isolated syndrome meets the criteria for high risk of conversion to multiple sclerosis, then initiation of disease-modifying treatment may be advised. Early initiation of disease-modifying therapy within 6 months of a first demyelinating event is associated with a reduction in the risk of long-term disability accrual compared to longer intervals before initiation of treatment (11). Disease-modifying drugs for multiple sclerosis, including interferon beta-1a IM (Avonex®), subcutaneous interferon beta-1b (Betaseron®), subcutaneous interferon-beta 1a (Rebif®), peginterferon-beta 1a (Plegridy®), glatiramer acetate (Copaxone®), teriflunomide (Aubagio®), fingolimod (Gilenya®), siponimod (Mayzent®), ozanimod (Zeposia®), ponesimod (Ponvory®), dimethyl fumarate (Tecfidera®), diroximel fumarate (Vumerity®), and monomethyl fumarate (Bafiertam®) are FDA-approved for patients with relapsing forms of multiple sclerosis, including clinically isolated syndrome. Natalizumab, alemtuzumab, ocrelizumab, ofatumumab, ublituximab, cladribine, and mitoxantrone have not been tested or approved in clinically isolated syndrome patients.

Randomized controlled trials showed reduced clinical events in individuals with radiologically isolated syndromes treated with dimethyl fumarate or teriflunomide (47). Correct diagnosis and risk stratification for patients with radiologically isolated syndrome are important to clarify favorable benefit and risk profiles of potential disease-modifying treatments.

Symptomatic treatments may benefit patients with residual neurologic dysfunction. Baclofen or tizanidine may be used for spasticity. Dalfampridine may be used for patients with slowed walking due to multiple sclerosis. Bladder antispasmodics such as tolterodine, oxybutynin, darifenacin, trospium, solifenacin, or mirabegron may be used for bladder urgency and incontinence, and bethanechol may help with incomplete bladder emptying due to bladder atonia. Referral to urology is advised for patients with complex bladder dysfunction. Cognitive impairments may be treated with donepezil, rivastigmine, galantamine, or memantine, though clinical benefits appear small at best. Mood disorders may be treated with tricyclic antidepressants (which may also help with bladder urgency and insomnia), selective serotonin inhibitors, or serotonin-norepinephrine reuptake inhibitors. Fatigue is common and may improve with behavioral strategies with occupational therapists or symptomatic therapies such as amantadine, amphetamine salts, modafinil, or armodafinil. Neuropathic pain may respond to antiepileptic medications such as gabapentin, carbamazepine, or pregabalin. Rehabilitation specialists, including physiatry, physical therapy, occupational therapy, and cognitive rehabilitation, are also incorporated in comprehensive multiple sclerosis care.

Table 1. Symptomatic Treatment of Common Multiple Sclerosis Symptoms

	Treatment Options	Caution
Fatigue	Minimize sedating medications
	Review sleep hygiene and screen for sleep disorders
	Depression screen, check iron, B12, and thyroid	Low evidence of benefit for medications
	Exercise regimen and energy conservation techniques with occupational therapy
	Cooling devices when triggered by heat	Start medications at low dose
	Amantadine 100mg morning and early afternoon	Risk of hallucinations
	Modafinil or armodafinil in morning	Caution if cardiac disease
	Methylphenidate or amphetamine compounds	Caution if cardiac disease
Cognitive impairment	Depression screen	No evidence of benefit with acetylcholinesterase inhibitors or memantine (unless coexistent Alzheimer-type dementia)
	Manage co-morbidities
	Limit polypharmacy
	Encourage lists, use of calendar
	Physical, mental, and social engagement
Pseudobulbar affect	Tricyclic antidepressant	Risk of cognitive impairment
	SSRI or SNRI
	Dextromethorphan or quinidine
Depression or anxiety	Cognitive behavioral therapy or counseling
	SSRI or SNRI
	Buproprion	May increase anxiety
Weakness	Physical or occupational therapy
	Ankle foot orthosis for foot drop
	Functional electronic stimulation for foot drop	Expensive, limited coverage
Spasticity	Stretching and home exercise program
	Physical or occupational therapy
	Baclofen, tizanidine or gabapentin	Sedation risks, constipation
	Diazepam	Sedation and dependence risks
	Dantrolene	Liver toxicity
	Oral nabiximols spray	Not available in the United States
	Botulinum toxin injections	Weakness of injected muscles
	Intrathecal baclofen pump	Device malfunction or infection
Gait impairment	Physical therapy and home exercise program
	Assistive devices: cane, walker, or motorized wheelchair
	Dalfampridine	Avoid if CrCl <51 or seizure history
Painful dysesthesias	Gabapentin or pregabalin	Sedation, weight gain, depression
	Carbamazepine, oxcarbazepine	Sedation, hyponatremia
	Lacosamide or lamotrigine	Sedation
Overactive bladder	Check urinalysis and urine culture
	Pelvic floor physical therapy
	Scheduled voiding
	Avoid caffeine, alcohol, tobacco, and carbonated drinks
	Anticholinergic medications	Cognitive side effects, constipation
	Intravesical botulinum toxin injections or bladder stimulator with urology or urogynecology	Urinary retention Device infection
Urinary retention	Check post-void residual (PVR)
	Urology referral for intermittent self-catheterization if PVR >100
	Manage constipation
	Urinary tract infection surveillance
	Tamsulosin	Not FDA-approved for females
	Bladder stimulator with urology or urogynecology	Device infection
Sexual dysfunction	Medication review (SSRI, SNRI, beta-blocker, etc)
	Adaptive positioning, lubrication, or stimulators
	Phosphodiesterase inhibitors for males with erectile dysfunction	Hypotension
Constipation	Bowel regimen with hydration, fiber, and exercise
	Polyethylene glycol 3350
	Prucalopride	Abdominal pain, diarrhea
	Linaclotide	Diarrhea, abdominal pain

Lifestyle adjustments. Exercise is beneficial for multiple sclerosis patients. It may improve lower extremity strength, improve fatigue and mood, lessen spasticity, and improve balance (40). As patients increase core body temperature with exercise, they may experience transient worsening of preexisting symptoms due to temperature-dependent effects on nerve conduction (Uhthoff phenomenon), though symptoms will return to baseline without any worsening disability or permanent neurologic injury. Small studies have demonstrated potential benefit in fatigue severity with dietary changes and in better pain control and mood with mindfulness training.

Outcomes

High-dose steroid administration for acute demyelinating events, including a clinically isolated syndrome, is associated with more rapid improvement in symptoms, though eventual recovery is not significantly different from untreated patients at 6 months (06). Common transient high-dose steroid side effects include insomnia, mood changes, elevated blood sugars, weight gain, and swelling.

Multiple sclerosis disease-modifying medications prolong the time to a second demyelinating event and conversion to clinically definite multiple sclerosis and reduce the risk of long-term disability in high-risk patients with clinically isolated syndrome. Long-term follow-up of patients with a first demyelinating event demonstrates that individuals with Progression Independent of Relapse Activity (PIRA) within 5 years have a 26 times increased risk of developing severe disability (57). The risk of PIRA was increased with baseline older age. Treatment side effects and complications vary by medication. Common interferon side effects include transient flu-like symptoms (myalgias, chills, fatigue, headache), injection site reactions, elevated hepatic transaminases, leukopenia, or worsening depression. Glatiramer side effects include injection site reactions, lipoatrophy, and immediate post-injection reactions. Teriflunomide is associated with elevated hepatic transaminases, intermittent nausea and diarrhea, peripheral neuropathy, and temporary hair thinning.

Fingolimod, siponimod, ozanimod, and ponesimod are associated with first-dose bradycardia, treatment-related lymphopenia, elevated hepatic transaminases, and rare infections, including fungal meningitis and progressive multifocal leukoencephalopathy. Dimethyl fumarate, monomethyl fumarate, and diroximel fumarate are associated with intermittent flushing, gastrointestinal upset, diarrhea, and nausea. Six percent of patients may develop persistent leukopenia, which has been associated with a risk of progressive multifocal leukoencephalopathy. Natalizumab is associated with infusion or allergic reactions, elevated hepatic transaminases, and risk of progressive multifocal leukoencephalopathy. Ocrelizumab, ublituximab, and off-label rituximab are associated with transfusion reactions, elevated risk of upper respiratory infections, rare cases of progressive multifocal leukoencephalopathy, and reduced vaccine responsiveness. Ofatumumab has a similar mechanism of action but is administered subcutaneously. Alemtuzumab is approved for patients who have failed standard multiple sclerosis therapies and is associated with a risk of infusion reactions, secondary autoimmune disorders, progressive multifocal leukoencephalopathy, and potential risk of malignancy.

Treatments on the horizon. Emerging therapies for multiple sclerosis include Bruton tyrosine kinase inhibitors, stem cell transplantation, and many others. Results of trials demonstrating the benefit of these therapies in clinically isolated syndrome patients are lacking.

Special considerations

Pregnancy

The risk of demyelinating attacks, including clinically isolated syndrome, is increased in the postpartum period (within approximately 6 months after delivery) and offsets an otherwise decreased risk of multiple sclerosis attacks during the second and third trimester of pregnancy. Steroids should be avoided during the first trimester but may otherwise be used for acute demyelinating attacks during pregnancy. Glatiramer is not associated with fetal harm in animal data. The risk of fetal harm appears low with interferons with possible low birth weight. Oral therapies, including teriflunomide, sphingosine phosphate modulators (fingolimod, siponimod, ozanimod, and ponesimod), fumarates (dimethyl fumarate, diroximel fumarate, and monomethyl fumarate), and cladribine should be avoided during pregnancy due to risk of fetal malformations. Breastfeeding safety information for medications is available via LactMed and can be accessed at the following site:https://www.ncbi.nlm.nih.gov/books/NBK501922/?report=classic). Exclusive breastfeeding may be associated with a reduced risk of postpartum relapse.

In women with a clinically isolated syndrome or early multiple sclerosis, oral contraceptive use does not impact the risk of a second attack or disability accrual (42). The long-term disability trajectory of women with clinically isolated syndrome or multiple sclerosis is not significantly altered by menopause (43).

Anesthesia

Any physiologic stressor such as fever, illness, or surgery may temporarily worsen prior deficits (recrudescence or pseudo-relapse), including those that may have previously been subclinical, without any clear worsening of the underlying disease. No contraindications or special precautions are warranted for surgery or anesthesia, except in individuals with advanced disability who may have a more prolonged post-procedural recovery. Multiple sclerosis disease-modifying therapies may be continued perioperatively.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Elizabeth A Hartman MD

Dr. Hartman of the University of Nebraska has no relevant financial relationships to disclose; her spouse owns Amgen stock.
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Editor

Anthony T Reder MD

Dr. Reder of the University of Chicago received honorariums from Biogen Idec, Genentech, Genzyme, and TG Therapeutics for service on advisory boards and as a consultant and stock options from NKMax America for advisory work.
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Patient Profile

Age range of presentation: Clinically isolated syndrome

Typical: 18 to 35 years

Atypical: 6 to 17 and 60 to 80 years
Sex preponderance: female>male, >2:1
Heredity: heredity may be a factor, twin studies suggest 33% risk of demyelinating disease
Population groups selectively affected: Northern Europeans

Black Americans
Occupation groups selectively affected: none

ICD & OMIM codes

ICD-10: Acute disseminated encephalomyelitis: G04.0

Demyelinating disease of central nervous system, unspecified: G37.9

Multiple sclerosis: G35

Neuromyelitis optica [Devic]: G36.0

Optic neuritis: H46

Acute transverse myelitis in demyelinating disease of central nervous system: G37.3
ICD-11: Isolated demyelinating syndromes of the central nervous system: 8A41

Other specified isolated demyelinating syndromes of the central nervous system: 8A41.Y

Acute disseminated encephalomyelitis: 8A42

Multiple sclerosis or other white matter disorders, unspecified: 8A4Z

Neuromyelitis optica: 8A43

Optic neuritis: 9C40.1

Transverse myelitis: 8A41.0
OMIM: Multiple sclerosis, susceptibility to; MS: #126200

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Clinically isolated syndrome

Associated Disorders

Devic disease
Multiple sclerosis
Neuromyelitis optica

Differential Diagnosis

multiple sclerosis
neuromyelitis optica (Devic disease)
systemic lupus erythematous
Sjögren syndrome
antiphospholipid antibody syndrome
- Behçet disease
- Tumor necrosis factor inhibitor use
- human T-cell lymphotropic virus-1 (tropical spastic paraparesis)
- tuberculosis
- HIV
- syphilis
- hepatitis
- Bartonella henselae
- progressive multifocal leukoencephalopathy
- acute disseminated encephalomyelitis
- Benign neoplasms
- malignant neoplasms
- Paraneoplastic syndromes (eg, cerebellar degeneration associated with anti-Yo antibodies)
- ischemic stroke
- hemorrhagic stroke
- Fabry disease
- CADASIL
- Susac syndrome (retinocochleocerebral vasculopathy)
- vitamin B12 deficiency
- copper myelopathy
- folate deficiency
- vitamin E deficiency
- Central pontine myelinolysis
- hereditary leukodystrophies
- adrenoleukodystrophy
- adrenomyeloneuropathy
- metachromatic leukodystrophy
- Alexander disease
- Canavan disease
- cerebrotendinous xanthomatosis
- Refsum disease
- Pelizaeus-Merzbacher disease
- globoid cell leukodystrophy
- Leber hereditary optic neuropathy
- sarcoidosis
- neurosarcoidosis
- Marchiafava-Bignami disease

Also Relevant

Clinical trials in multiple sclerosis
Interferon beta 1b
Multiple sclerosis: neuroimmunology
Multiple sclerosis: treatment of its symptoms
Neuromyelitis optica spectrum disorder
- Optic neuritis
- Optical coherence tomography in multiple sclerosis and neurologic disorders
- Transverse myelitis

Clinically isolated syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Table 1. Symptomatic Treatment of Common Multiple Sclerosis Symptoms

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

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Also in This Category

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Giant cell arteritis

Chronic inflammatory demyelinating polyradiculoneuropathy

Autoimmune autonomic neuropathy

HTLV-1 associated myelopathy

Myositis and cancer

Paraneoplastic retinopathy

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