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 (25). 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 (49). Specific symptoms vary based on 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, onset of unilateral blurred vision accompanied by pain with eye movements and a normal ophthalmologic examination is suggestive of 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 and/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 (35). 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 (50; 49; 59).

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.

Mild cognitive dysfunction may also be present in a subset of patients with early demyelinating disease. A study revealed that 24% of clinically isolated syndrome patients had abnormal testing results on at least one portion of the Brief Repeatable Battery (53); the prevalence of cognitive deficits appears similar between patients with radiologically isolated syndrome compared to clinically isolated syndrome (26). Functional MRI studies reveal adaptive changes to cognitive networks in clinically isolated syndrome patients, which progress with disease duration (30).

A radiologically isolated syndrome describes an asymptomatic individual with brain MRI lesions consistent with demyelination (44). Often individuals undergo a brain MRI for research after an injury or other unrelated reason and incidentally are noted to have lesions which are consistent with demyelination. Demyelinating lesions are typically in periventricular, juxtacortical, infratentorial, or spinal cord locations; 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 are usually nonenhancing but occasionally can be associated with abnormal enhancement on T1 imaging after gadolinium contrast administration. The present of the central vein sign and chronic active lesions with a paramagnetic rim may increase multiple sclerosis diagnostic criteria specificity but are not yet validated (15).

Prognosis and complications

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 2-year follow-up, depending on diagnostic criteria applied (11). 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 (45). 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 (16). 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 (60). 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 (34). 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 (61).

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 elevated risk of eventual development of secondary progressive multiple sclerosis (06; 07). 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 (47). In multiple sclerosis patients, 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 (09). 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 (19).

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 (51). Longer exposure to disease modifying therapy was associated with 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 (23; 08; 22; 52). 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 (60). Natural history studies reveal a strong correlation between the number of relapses in the first two years of disease and time to future disability (55). Thus, early control of disease activity may have a benefit in time to 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 (48).

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 history of controlled hypertension developed right retro-orbital discomfort associated with mild blurred vision “as if looking through a film” with worsening over next two days to inability to read with 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 three days) and referred to Neurology for further work up. 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 right optic nerve with slight T2 hyperintensity, and a non-enhancing single, rounded 4 mm subcortical left frontal white matter hyperintensity. 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. Patient deferred cerebrospinal fluid testing.

The patient was diagnosed with clinically isolated syndrome based on demyelinating event of optic neuritis and lack of dissemination in time or space. After discussion of the risk of development of multiple sclerosis and 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 new symptoms were noted by patient. The patient’s vision improved to 20/30 at 6-month follow-up with mild increased blurred vision noted by patient when exercising, with stable brain MRI. A new, nonenhancing periventricular T2 hyperintensity and an enhancing cerebellar lesion were noted on 12-month follow-up brain MRI. After discussion, patient 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 varies 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 prior to clinically isolated syndrome onset (12). Childhood and adolescent obesity is associated with increased susceptibility to multiple sclerosis (18). 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 (20). 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, in 56.1% of multiple sclerosis patients, and in 22.7% of healthy controls and, thus, argues against CCSVI as the etiology of demyelinating disease (66). Further, a randomized prospective trial with venous angioplasty failed to show any benefit (57).

Epidemiology

Data on overall incidence of clinically isolated syndromes are lacking, but one may extrapolate clinically isolated syndrome incidence based on multiple sclerosis incidence. However, because not all clinically isolated syndromes represent multiple sclerosis, one should assume that clinically isolated syndrome incidence rates are higher than multiple sclerosis. Incidence of multiple sclerosis varies geographically and has been noted to be higher in regions that are farther from the equator. Prevalence data found that in the United States in 2017, the prevalence of multiple sclerosis was 363 cases per 100,000, totaling 913,925 adults with multiple sclerosis (63). A regional Canadian study found the prevalence of multiple sclerosis to be 2.65 per 1000 in 2013 (54). A prior population-based study in the United States in Olmstead County, Minnesota from 1985 to 2000 revealed an overall multiple sclerosis incidence of 7.5 per 100,000 (32). The incidence was 10.4 per 100,000 women compared to 4.5 per 100,000 men. Incidence rates are similar in European countries, with an increased incidence noted in northern latitude countries (17). Lower incidence rates of multiple sclerosis are presumed in some Asian countries based on prevalence data. Very low multiple sclerosis prevalence (less than 1 per 100,000) is noted in India, Taiwan, and Hong Kong compared to low prevalence (1.8 to 2 per 100,000) in Korea, Thailand, and Malaysia and higher prevalence (8 to 42 per 100,000) in Saudi Arabia, Kuwait, and Jordan (24). Low incidence rates of demyelinating diseases in some underdeveloped countries may be inaccurate due to poor health care access and public health data.

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, prevention of 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 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 equator, Epstein-Barr virus infection, genetic factors, female gender, and childhood obesity (28; 18). Abstinence or discontinuation of tobacco use may reduce 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 (62). A randomized trial of vitamin D3 treatment in clinically isolated syndrome patients compared to placebo failed to demonstrate immunologic, MRI, or clinical evidence of benefit (41). 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 (40).

Differential diagnosis

Confusing conditions

A clinically isolated syndrome implies that a patient has a clinical symptom present. This is different from a radiologically isolated syndrome, where demyelinating lesions are found without any associated symptom. 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. Revisions to the categorization of the clinical course of multiple sclerosis advocate for clinically isolated syndromes, but not radiologically isolated syndromes, to be included in the spectrum of multiple sclerosis phenotypes (31). The rate of conversion from a clinically isolated syndrome to clinically definite multiple sclerosis varies from 56% to 82% in prospective studies (04; 14).

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 and/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 (21). 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 (65). 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 (64). 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 (58). 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 (39).

Sarcoidosis is a granulomatous disorder that is confirmed by the presence of noncaseating granulomas in tissue biopsy and 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 (20). 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 is also seen in association with 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 six 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 prior to 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 (13).

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 are generally of a more subacute onset. Central pontine myelinolysis is a syndrome of noninflammatory demyelination that typically develops after rapid correction of hyponatremia leads 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 (56). 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.

Diagnostic workup

• Detailed history to screen for prior events, careful neurologic examination, neuroimaging with brain and/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 detailed history, exam, 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, or others. MRI interpretation should be done with extra caution in patients with migraine with aura 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 one 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/cortical, infratentorial, or spinal cord). Dissemination in time is met when two more historical attacks can be confirmed by clinical exam, or at least one historical attack is confirmed by clinical exam 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 MS lesions on MRI, if a new T2 or enhancing MS 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 one 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/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 (42). Clinically isolated syndrome patients with lesions on baseline brain MRI have an approximately 80% chance of developing multiple sclerosis in 10 years (45). 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.

Research by a European multicenter collaborative reveals that dissemination in time is more specific for clinically definite multiple sclerosis than dissemination in space, and that characteristic locations of lesions (ie, quality) was more important than the number (quantity) of lesions (36).

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. 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 (61). 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.

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

Cerebral angiogram may be considered in cases where vasculitis, vasospasm, intracranial stenosis, or vascular malformation is suspected, but is not typically performed for evaluation of 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.

In individuals with low risk clinically isolated syndrome or radiographically isolated syndrome, or those with atypical features, observation and serial monitoring is typically recommended. Clinical follow up as well as serial MRIs at an initial 3- to 6-month interval, followed by every 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 equivalent oral prednisone dose of 1250 mg daily for three to seven days (38). High-dose steroid treatment may be followed by a brief oral steroid (often prednisone) taper, though there are no data to support 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 (10). 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 criteria for high risk of conversion to multiple sclerosis, then initiation of disease-modifying treatment may be advised. 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.

In women with a clinically isolated syndrome or early multiple sclerosis, oral contraceptive use does not impact risk of second attack or disability accrual (46).

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.

Lifestyle adjustments. Exercise shows benefit for multiple sclerosis patients. Exercise may improve lower extremity strength, improve fatigue and mood, lessen spasticity, and improve balance (43). 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. Common transient high dose steroid side effects include insomnia, mood changes, elevated blood sugars, weight gain, and swelling.

Multiple sclerosis disease-modifying medications as noted above prolong time to second demyelinating event and conversion to clinically definite multiple sclerosis in high-risk clinically isolated syndrome patients. 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 side reactions, lipoatrophy, and immediate postinjection reactions. Teriflunomide is associated with elevated hepatic transaminases, intermittent nausea and diarrhea, peripheral neuropathy, and temporary hair thinning.

Fingolimod, siponimod, and ozanimod are associated with first-dose bradycardia, treatment-related lymphopenia, elevated hepatic transaminases, and rare infections, including fungal meningitis and progressive multifocal leukoencephalopathy. Dimethyl 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 risk of progressive multifocal leukoencephalopathy. Natalizumab is associated with infusion or allergic reactions, elevated hepatic transaminases, and risk of progressive multifocal leukoencephalopathy. Ocrelizumab 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 though is administered subcutaneously. Alemtuzumab is approved for patients who have failed standard multiple sclerosis therapies and is associated with 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. To date, results of trials demonstrating 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 six months after delivery) and offsets an otherwise decreased risk of multiple sclerosis attacks during the second and third trimester of pregnancy. Steroids use 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. Risk of fetal harm appears low with interferons with possible increase 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.

Anesthesia

Any physiologic stressor such as fever, illness, or surgery may result in temporary worsening of 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.