Multiple sclerosis (MS) is an autoimmune central nervous system (CNS) demyelinating disease characterized by inflammatory clinical relapses and gradual neurodegeneration. The etiology of MS is multifactorial and involves both genetic and environmental factors. MS diagnosis is made on clinical and imaging grounds. The basic paradigm was first introduced in the 1960s and is referred to as Schumacker’s1 criteria after its first author. Schumacker set out 6 criteria for the diagnosis of definite MS:
Age between 10 and 50 years
Presence of objective clinical signs
Lesions being predominantly in the white matter
Two or more lesions in the CNS separated in space
The attacks being separated in time
Episodes lasting more than 24 hours and spaced more than one month apart
Documented progression for more than 6 months.
The rule out of other pathologies
These have been revised (current criteria = McDonald Criteria—Table 43-1)2 with the advent of newer diagnostic modalities, but the paradigm remains the essence of MS diagnosis. The steps to diagnose MS are as follows:
Take history, examine the patient, and document compatibility of the signs and symptoms with MS. Certain common presentations increase suspicion for the disease.
Document the presence of white matter lesions, which are separated by time and space on imaging and clinical grounds.
Rule out mimics of MS.
Be aware of MS variants.3
2010 McDonald Criteria for the Diagnosis of Multiple Sclerosis8
| Clinical Presentation | Additional Data Needed for Dx |
|---|---|
| ≥2 attacks, objective clinical evidence of ≥2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack | None |
| ≥2 attacks, objective clinical evidence of 1 lesion | Dissemination in space demonstrated by MRI or 2nd clinical attack |
| 1 attack, objective clinical evidence of ≥2 or more lesions | Dissemination in time demonstrated by MRI or second clinical attack |
| 1 attack, objective clinical evidence of 1 lesion (clinically isolated syndrome) | Dissemination in space and time demonstrated by MRI or second attack |
| Insidious neurologic progression suggestive of PPMS | One-year disease progression (retrospective or prospective) AND 2 or 3: DIS in the brain, spinal cord, or OCBs |
The goals of treatment are to reduce long-term disability and treat symptoms and exacerbations as follows:
Institute disease-modifying medication.
Treat exacerbations.
Treat symptoms that arise from chronic changes caused by multiple exacerbations as well as progressive disease.
This chapter is organized around these themes:
Part 1 explores the diagnosis of MS.
Part 2 concentrates on mimic of MS.
Part 3 concentrates on treatment of exacerbations.
Part 4 outlines disease management.
Part 5 address MS and reproductive issues.
A clinically isolated syndrome (CIS) is defined as a clinical episode that lasts for more than 24 hours and is caused by demyelination in the CNS. At an early stage, the patient may not fulfill the criteria for the diagnosis of MS. It is important to note that not all patients with CIS progress to develop MS. The most common clinically isolated syndromes are brainstem demyelination, optic neuritis, and transverse myelitis.
CASE 43-1
A 27-year-old woman presents for the evaluation of double vision. She complains that for the last 2 days whenever she gazes to the left, objects in her field of view appear to split into 2. The motor, sensory, cerebellar, reflex, and gait examinations are normal. On cranial nerve examination, the patient saccades normally to the right but when asked to look to the left, you notice incomplete adduction of the right eye and nystagmus in the abducting left eye.
Internuclear ophthalmoplegia (INO) is a disorder of eye movement characterized by a lack of synergy between the 2 eyes during horizontal saccades. It is caused by lesions of the medial longitudinal fasciculus (MLF) in the brainstem. In this case, the right MLF is dysfunctional. When the right eye abducts, the sixth cranial nerve communicates with the left oculomotor nucleus via the healthy left MLF, so that the right gaze is normal. On the other hand when the left eye abducts, a dysfunctional MLF is unable to prompt the adduction of the right eye. The nystagmus on the left side is an attempt by the left eye to correct for the double vision.4
The most common causes of INO are multiple sclerosis (MS) and brainstem vascular lesions. Given the age of this patient, there is a high index of suspicion for MS.
Multiple sclerosis presents in a number of well-characterized syndromes that, although commonly associated with it, are not pathognomonic of it. These include:
Visual problems: unilateral optic neuritis
Diplopia: internuclear ophthalmoplegia (INO) and other ophthalmoplegias
Limb incoordination: ataxia with multidirectional nystagmus
Cranial neuropathies:
Sixth nerve (CN VI) palsy
Facial myokymia or facial weakness
Trigeminal neuralgia or facial numbness
Sensory symptoms
Transverse myelitis:
Partial myelopathy
Lhermitte’s sign
Progressive spastic paraplegia
Urinary and/or erectile dysfunction
Mild subcortical cognitive impairment
MS can very rarely present in a fulminant way. Several fulminant variants of MS have been described:6
Balo’s concentric sclerosis: The disease presents with symptoms suggestive of a mass-occupying lesion. Masses of concentric rings of myelination and demyelination are found on MRI imaging. The course is typically weeks to months. It should be treated under specialist MS care in a tertiary referral center.
Marburg variant of MS: This is essentially an acute progressive form of MS that presents with symptoms of MS as well as encephalitis such as headache, nausea, vomiting, and seizures. Again this is an emergency outside the scope of the nonspecialist.
Schilder’s disease: This is a fulminant pediatric form of MS that affects mostly the centrum semiovale and adjacent areas.
Clinical presentation:
Symptomatology: diplopia, ataxia, myelopathy, and cranial neuropathy
Associated symptoms: fatigue, affective disorders, and heat sensitivity
Nonmodifiable risk factors:7
Female gender: Most autoimmune diseases are more common in women. In this case, the female to male ratio is of the order of 2:1.
White race/ethnicity (especially Scandinavian ancestry)
High socioeconomic status
Family history: The presence of MS in first-degree relatives increases the risk of MS significantly. Identical twins where one twin has MS have 30% chance of having MS.
Modifiable risk factors:
Latitude: MS is more common in people who have spent their first 15 years of life in northerly latitudes (in the Northern Hemisphere).
Viral infections: There is an epidemiological correlation with certain viral infections.
Vitamin D deficiency
Smoking
In an appropriate patient, with a history consistent with a demyelinating event and/or objective evidence of a lesion affecting the CNS white matter, MRI is invaluable in confirming the diagnosis. MRI can help confirm dissemination of lesions in space and time. Cranial, cervical, and thoracic MRIs are performed (Figure 43-1).
Dissemination in space is demonstrated by ≥1 characteristic T2 lesions in at least 2 of 4 areas of the CNS: periventricular, juxtacortical, infratentorial, or asymptomatic spinal cord lesion (see Table 43-2).
Dissemination in time is demonstrated by a new T2 or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the scans, or the simultaneous presence of an asymptomatic gadolinium-enhancing and nonenhancing lesion at any time (see Table 43-3).8
MRI Criteria for Dissemination in Space8
| Dissemination in Space Can Be Demonstrated by > 1 T2 lesion in at Least 2 of 4 Areas of the CNS: |
| Periventricular |
| Juxtacortical |
| Infratentorial |
| Spinal cord |
| If the patient has a brain stem or spinal cord syndrome, the symptomatic lesion is excluded from the criteria and does not contribute to lesion count. |
MRI Criteria for Dissemination in Time8
| Dissemination in time can be demonstrated by |
| New T2 or gadolinium-enhancing lesion on follow-up MRI compared to a previous scan |
| Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions |
Typical MS T2 hyperintense lesions are usually >3 mm in size.
Infratentorial lesions (those below the tentorium cerebelli) are often close to the pial surface (as opposed to the deep midline lesion more typical of vascular lesions).
Gadolinium-enhancing MS lesions are often incompletely enhancing.
MS-related lesions of the spinal cord are often small (usually <1 vertebral segment), and often involve only a portion of the cross-sectional area of the spinal cord with a preference for the dorsal columns. Spinal lesions that span several vertebral segments are often associated with neuromyelitis optica (NMO) or Devic’s disease.
Cerebrospinal fluid (CSF) examination’s routine use in a patient presenting with a characteristic history and characteristic appearing MRI is not necessary. Its use can be considered in patients in whom the diagnosis is not clear, or for whom an alternative diagnosis is being considered. The common CSF findings may include:
Cell count: often normal, rarely >50 WBC/mm3.
CSF glucose is normal.
Oligoclonal bands are suggestive of autoimmune disease. If they are present in the CSF and not plasma then their presence points to an intra-axial autoimmune condition such as MS. But other causes of upregulated CNS immune system may present with oligoclonal bands. Some of these include viral infections (HIV, viral encephalitis), syphilis, Lyme disease, systemic lupus erythematosus (SLE), neuromyelitisoptica (NMO), acute disseminated encephalomyelitis (ADEM), vasculitis, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and neurosarcoidosis.
The presence of OCBs is associated with an increased risk of a future clinical relapse.9
Evoked potentials (EPs) detect slowing of electrical conduction in the CNS by looking at summed EEG responses to sensory stimulation. The presence of slowing of electrical conduction is usually the result of demyelination, and the demonstration of such slowing can be interpreted by the clinician as the presence of a “second lesion.” So, its utility is when a second lesion is required to make a diagnosis of MS. There are three types of sensory EPs, which can be used: visual evoked potentials (VEPs), brainstem auditory evoked potentials (BAEPs), and somatosensory evoked potentials (SSEPs). The only one routinely used in clinical practice of MS is the VEPs.10
A broad differential diagnosis should be considered (while keeping in mind that MS is a common disorder):
Metabolic workup: TSH, vitamin B12, folate, methylmalonic acid, and homocysteine.
Autoimmune workup: ANA, ESR, and RF
Infectious causes: in selected cases, Lyme disease, HIV and HTLV-1 should be ruled out.
ACE levels for sarcoidosis, and lupus anticoagulant, cardiolipin, IgG and IgM antibodies, and IgG and IgM beta 2 glycoprotein 1 antibodies for the antiphospholipid antibody syndrome, in selected cases.
In younger patients, leukodystrophies should be considered.
CASE 43-1 (continued)
A contrast-enhanced cranial magnetic resonance imaging (MRI) is notable for a gadolinium-enhancing lesion in the dorsal pons, two ovoid-shaped periventricular lesions, one right parietal juxtacortical lesion, and one left frontal incompletely gadolinium-enhancing lesion approximately 3 mm in size. The spinal MRIs did not show any lesions. CSF study shows normal cell count and the presence of oligoclonal bands.
The mnemonic VITAMINS is used by the MS society to enumerate the differential diagnoses of MS:
Vascular: subcortical vascular disease, MELAS, and CADASIL
Infections: HIV and HTLV-1 myelopathy, PML, Lyme, and syphilis
Traumatic demyelination (eg, spine)
Autoimmune: neuromyelitisoptica (NMO), acute disseminated encephalomyelitis (ADEM), vasculitis, sarcoidosis, Behcet’s disease, and SLE
Metabolic: B6 and B12 deficiency, radiation, hypoxia, and central pontine myelinolysis (CPM)
Ideopathic/genetic: leukodystrophies and neurodegenerative ataxias
Neoplastic: metastases, CNS lymphoma, glioma, and paraneoplastic encephalitis
pSychiatric: conversion disorder (functional neurological symptom disorder)11
CASE 43-1 (continued)
You decide that the patient does not have vascular risk factors or a familial history of the same. The CSF does not show an evidence of infection. The lesions are not characteristic of neoplastic lesions. The labs rule out vitamin deficiencies. You find her symptoms credible and diagnose her with multiple sclerosis.
CASE 43-2
A 28-year-old woman presents for the evaluation of blurred vision. The patient reports that when she woke up in the morning, she was having a difficult time seeing out of her right eye. If she closed her right eye, she could see fine out of the left eye. If she closed the left eye, her vision was blurred. She initially associated these symptoms with a problem with her contact lenses, but as the problem was not resolving, she went to see an ophthalmologist, who referred her to the emergency department (ED). Her examination is notable for decreased color saturation of the right eye (the color red did not appear as strongly red with the right eye as it did the left), and the presence of a right afferent pupillary defect (RAPD).
Optic neuritis refers to primary inflammation of the optic nerve.12
Optic neuritis is the presenting feature in 15–20% of patients eventually diagnosed with multiple sclerosis (MS) and occurs at some time during the disease course in as many as 50% of patients.
Subacute visual loss (median visual acuity in the affected eye of 20/60, progressing over the course of hours to days), dyschromatopsia (difficulty perceiving colors, particularly red, which may appear less red, orange, less intense or “washed out”), and pain with eye movement.
An RAPD noted on the swinging light test is almost always present (see also: Chapter 8, The Neurologic Examination and Chapter 25, Approach to Acute Visual Changes, Abnormal Eye Movements and Double Vision). The absence of a RAPD should challenge the examiner to consider alternative diagnoses, such as retinal disease.
Visual-field loss is typical and classically presents as a central scotoma (loss of central vision) or blur, although various descriptions of vision loss can occur. Altitudinal defects should raise concern for an alternative diagnosis such as anterior ischemic optic neuropathy (AION).
Pain is present in the overwhelming majority of patients, is usually constant, and is worse with eye movement. Patients with AION rarely report pain.
The funduscopic examination may demonstrate a normal optic disk in the majority of patients (the optic neuritis is retrobulbar), swelling of the optic disk (papillitis) may occur, but hemorrhages should not be present.13
Imaging: Evaluation should include contrast-enhanced cranial MRI with fat saturation imaging of the orbits. MRI may show enhancement or enlargement of the optic nerve. However, the main role of MRI is not to “confirm” optic nerve involvement (as the diagnosis is made off of clinical findings) but to search for the presence of clinically silent demyelinating lesions to suggest a more global diagnosis such as MS.
Cerebrospinal fluid analysis: Testing of CSF is optional. CSF analysis is no longer included in the 2010 McDonald Criteria for the diagnosis of MS. If the neurohospitalist is concerned about an alternative diagnosis (such as neurosarcoidosis), CSF analysis can be considered.8
Visual evoked potentials (VEPs) can be considered to confirm an optic neuritis, although it is also not mandatory. VEPs typically show a prolonged latency and reduced amplitude compared to the contralateral unaffected eye.
Optic coherence tomography (OCT) likely has a role in the evaluation of optic neuritis, although its specific place has not yet been determined. OCT can quantify retinal nerve fiber layer (RNFL) thickness. The thickness of the RNFL may correlate with visual recovery. RNFL thickness of <75 µ m at 3–6 months after an episode of optic neuritis is often associated with incomplete recovery of visual field. Progressive loss of RNFL thickness between year 1 and year 2 is more often associated with MS rather than isolated optic neuritis. RNFL thickness of <50 is associated with neuromyelitis optica (NMO).14
Vascular: central or branch retinal artery occlusion
Infections: particularly herpes virus
Traumatic
Autoimmune: vasculitis with granuloma, NMO
Metabolic: nutritional deficiencies
Idiopathic/genetic: hereditary optic neuropathies such as mitochondrial diseases.
Neoplastic: compressive
pSychiatry: conversion disorder (functional neurological symptom disorder).
CASE 43-2 (continued)
An MRI is performed, which shows no other lesions in the brain. The CSF is normal, and the VEPs show the expected changes.
Not every patient who presents with a clinically isolated syndrome goes on to develop MS. Like all clinically isolated syndromes, the risk of progression to MS in optic neuritis depends on whether the deficits are multifocal or monofocal. An isolated optic neuritis with no evidence of “second lesion” on MRI has a low risk of progression to MS, whereas the presence of additional areas of demyelination on the MRI increases the chance of progression significantly.13
The standard of care is intravenous methylprednisolone: Intravenous (IV) methylprednisolone has been considered the “standard of care” for the treatment of optic neuritis since the Optic Neuritis Treatment Trial (ONTT). In the ONTT, patients received either oral prednisone at 1 mg/kg/day for 14 days or IV methylprednisolone 250 mg every 6 hours for 3 days followed by an oral course, or placebo. Patients receiving IV methylprednisolone improved faster than those receiving oral steroids or placebo (although the outcomes were the same regardless of treatment at 6 months), and those receiving oral steroids had twice the rate of recurrent optic neuritis compared to either the IV group or the placebo group. However, the results may have been entirely dose dependent, not “route-dependent.” IV methylprednisolone patients received a substantially higher equivalent dose than their oral prednisone counterparts.8 Some studies have suggested that high-dose oral steroids may be as effective as IV methylprednisolone.14,15
The treatment shortens recovery but does not change long-term outcomes: Treatment is not mandatory—most patients (95%) regain visual acuity of 20/40 or better by 12 months, regardless of treatment.14
There is no consensus on the optimal dose or duration of corticosteroids for the treatment of MS relapses: It is generally agreed that “high dose” is optimal—but there is no universal agreement as to what constitutes a high dose. Doses higher than 500 mg/day are generally preferred for courses usually ranging from 3 to 7 days.16
Refractory disease: For patients with severe visual loss due to optic neuritis refractory to high-dose corticosteroids, intravenous immunoglobulin (IVIG) may be considered. In a small study, IVIG administered at a dose of 400 mg/kg/day for 5 days, followed by once-monthly infusion (400 mg/kg) for 5 months, improved vision to normal or near normal (better than 20/30) in 78% of patients compared to similar return of vision in only 12.5% of the placebo group.17 Intramuscular (IM) adrenocorticotropic hormone (ACTH) gel may also be a treatment option for patients with an inadequate response or intolerance of IV or oral corticosteroids. In studies going back to the 1970s, ACTH has been shown to improve outcomes versus placebo.18
CASE 43-3
A 33-year-old woman presents for gait dysfunction. She hurt her back while lifting a box, prompting consultation with orthopedic surgery. A non-contrast cervical MRI was notable for 2 intramedullary T2 lesions of <1 vertebral segment in length, for which she was referred to Neurology. On questioning, the patient does report that she has noticed a sudden change in her walking since around the time of her injuring her back.
Transverse myelitis is an autoimmune mediated process that affects the spinal cord giving varying degrees of myelopathy. It presents with myelopathic signs and symptoms including weakness in the lower extremities, bladder dysfunction, sensory changes, and erectile dysfunction. The clinical course often peaks in 7–10 days before starting to improve.
More than half of the cases are thought to be postviral after respiratory and gastrointestinal infections. These are classified as idiopathic.
Most of the rest are caused by connective tissue disease and MS.
Most of the rest of etiologies and mimics may be remembered using the mnemonic VITAMINS:
Vascular: spinal cord infarct
Idiopathic/genetic: adrenomyeloneuropathy, etc.
Traumatic and radiation
Autoimmune: NMO, ADEM
Metabolic/Toxic: subacute combined degeneration of the cord due to B12 deficiency, copper deficiency, zinc toxicity (causing a copper deficiency myeloneuropathy), or nitrous oxide myelopathy
Infectious: tropical spastic paraparesis, infectious myelitis
Neoplastic: intramedullary tumors, extramedullary compression, paraneoplastic myelopathy
pSychiatric: conversion disorders (functional neurological symptom disorder)
As the name of the condition suggests, a diagnosis is predicated on 4 things:
TM is tranverse: That is, there should be bilateral signs and symptoms.
TM is a myelopathy:
There should a sensory level.
There should be myelopathic symptoms such as sensory, motor, and autonomic dysfunction.
TM is inflammatory: This is demonstrated by CSF pleocytosis OR elevated IgG index OR contrast enhancement on MRI imaging. If negative and still suspicious of the diagnosis then may repeat these tests in a week.
Rule out alternative explanations.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
