Chapter 21: Demyelinating Diseases of the Central Nervous System

This chapter focuses on the following central nervous system demyelinating diseases:

• Multiple sclerosis (MS)

• Neuromyelitis optica (NMO)

• Acute disseminated encephalomyelitis (ADEM)

• Optic neuritis

• Transverse myelitis

Optic neuritis and transverse myelitis may be caused by a primary central nervous system (CNS) demyelinating disease (e.g., MS, NMO), systemic autoimmune disease, or may occur in the setting of infection, following infection, or as paraneoplastic conditions.

Demyelinating diseases of the peripheral nervous system (e.g., acute inflammatory demyelinating polyradiculoneuropathy [AIDP] and chronic inflammatory demyelinating polyradiculoneuropathy [CIDP]) are discussed in Chapter 27.

Clinical Features of Multiple Sclerosis

Multiple sclerosis (MS) is a demyelinating disease of the CNS that occurs more commonly in young women and is more prevalent further from the equator. In its most common clinical course, patients have multiple flares of symptoms at multiple time points, and recover from these attacks to varying degrees (relapsing-remitting MS). Later in the disease, patients with a relapsing-remitting course may enter a period of progressive decline, a scenario referred to as secondary progressive MS. Primary progressive MS is the least common clinical phenotype of MS, and is typically a spinal cord predominant illness with steady clinical decline from the time of onset rather than relapses and remissions. Even more rarely, the disease may present fulminantly with large tumor-like lesions (Marburg variant, tumefactive demyelination, or Balo’s concentric sclerosis).

Flares of MS present as focal neurologic deficits that emerge and evolve over hours to days and usually resolve completely or near completely in subsequent days to weeks. Deficits are referable to central nervous system sites (brain, brainstem, optic nerve, cerebellum, and/or spinal cord) and can include a region of paresthesias and/or weakness, diplopia (due to disruption of ocular-motor white matter tracts in the brainstem), vertigo (due to demyelination of the cranial nerve 8 entry zone or in the cerebellum), optic neuritis, transverse myelitis, ataxia, and/or trigeminal neuralgia. Trigeminal neuralgia occurs due to demyelination at the trigeminal entry zone in the pons (the nerve itself is peripheral; see “Trigeminal Neuralgia” in Chapter 13). Although MS is not a common cause of trigeminal neuralgia, unilateral or bilateral trigeminal neuralgia in a young patient should lead to consideration of and evaluation for MS.

Between flares of MS, the accumulation of subclinical lesions may cause cognitive symptoms, neuropsychiatric symptoms, and/or fatigue, but progression of focal neurologic deficits between attacks is uncommon in relapsing-remitting MS. On neurologic examination, patients often demonstrate upper motor neuron signs on examination (e.g., hyperreflexia, clonus, Babinski’s sign[s]) even outside of regions of new or prior clinical symptoms due to subclinical lesions that have caused CNS damage without having caused clinical flares.

Other classic symptoms and signs of MS include:

• Uthoff’s phenomenon: recurrence or emergence of neurologic symptoms with heat (due to environmental temperature in the summer, hot bath, or exercise).

• L’hermitte’s sign: electrical sensation down the spine with forward flexion of the neck. This can occur in any type of cervical myelopathy and is not specific to MS.

• Internuclear ophthalmoplegia (INO) due to disruption of the medial longitudinal fasciculus (MLF) (see “Internuclear Ophthalmoplegia” in Chapter 11).

• Afferent pupillary defect due to prior optic neuritis. An afferent pupillary defect may be present even in patients who have not had a clear clinical episode of optic neuritis (see “Impaired Pupillary Constriction Due to a Lesion of Cranial Nerve 2” in Chapter 10).

Neuroimaging in Multiple Sclerosis

Neuroimaging is critical in the diagnosis of MS. Lesions of MS have a characteristic morphology and distribution, and imaging characteristics can help to determine whether lesions are acute or chronic. The classic radiologic features of MS are small, ovoid T2/FLAIR hyperintensities that are perpendicularly oriented to the lateral ventricles and corpus callosum. Viewed on a sagittal image, the white matter lesions radiating outward perpendicular to the corpus callosum have been referred to as Dawson’s fingers (Fig. 21–1). Acute lesions may demonstrate enhancement with gadolinium, often in an open ring (as compared to the complete ring of contrast enhancement seen with tumor and abscess) (see Fig. 21–4). The damage caused by lesions over time can lead to T1 hypointensities at sites of prior demyelination (T1 black holes). Lesions in the brainstem, cerebellar white matter, and spinal cord are common. In the spinal cord, MS lesions are typically small and peripherally located (Fig. 21–2) (as compared to the longitudinally extensive lesions of neuromyelitis optica, see “Neuromyelitis Optica” below and Fig. 21–3).

Other causes of subcortical white matter lesions include chronic microvascular white matter changes, leukodystrophies (see Ch. 31), CNS vasculitis, demyelinating lesions in systemic autoimmune disease (e.g., Sjögren’s syndrome), and CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy; see “Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukocencephalopathy (CADASIL) and Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukocencephalopathy (CARASIL)” in Chapter 19). However, in most cases the clinical context in these entities is distinct from that of a patient with MS.

Previously, multiple clinical attacks “disseminated in space and time” were required for diagnosis of MS. Now, the ability of MRI to determine the presence of both acute (enhancing) and chronic (non-enhancing) evidence of demyelination on allows for the diagnosis of MS to be made at the time of an initial attack with accompanying MRI features demonstrating dissemination in space and time. According to the 2010 McDonald Criteria (Polman et al., 2011):

• Dissemination in space is demonstrated clinically by history of two or more clinical demyelinating events affecting two different sites, or by MRI by demonstrating at least one lesion in two of the following four regions of the CNS: periventricular, juxtacortical, infratentorial, or spinal cord.

• Dissemination in time requires two or more clinical attacks, a new lesion on MRI compared to a prior MRI, or can even be demonstrated on a single MRI if there are both enhancing (acute) and nonenhancing (nonacute) lesions.

Clinically Isolated Syndrome

When a patient presents with a first demyelinating event typical of MS (e.g., optic neuritis, transverse myelitis, or another focal symptom with suggestive imaging correlate), this is called a clinically isolated syndrome (CIS). Patients presenting with CIS will of course want to know whether they have MS, and if not, what the risk of developing the disease is in the future and whether that risk warrants initiating treatment. If a patient has normal brain imaging in the setting of a first attack of optic neuritis or transverse myelitis, the risk of future development of MS is two to three times lower than if there are characteristic lesions on MRI, but is still in the range of 10%–30% (depending on the presenting syndrome; see “Optic Neuritis” and “Transverse Myelitis” below).

If dissemination in space and time can be proven by MRI at the time of a first attack, then the diagnosis of MS can be made by McDonald Criteria (Polman et al., 2011). Some practitioners advocate treating all such patients with disease-modifying therapy. Other practitioners individualize treatments based on the clinical picture and apparent lesion burden on MRI, treating some patients who appear to have the highest risk, while following others closely clinically and with serial imaging studies. Based on evidence that vitamin D deficiency may be associated with an increased risk of the development of MS, many practitioners initiate vitamin D supplementation in patients with CIS.

If patients with CIS do not meet clinical-radiologic criteria for MS, some practitioners elect to look for ancillary evidence that could support increased risk for subsequent development of MS such as cerebrospinal fluid (CSF) oligoclonal bands or visual evoked potentials.

Oligoclonal Bands

The presence of oligoclonal bands in the CSF that are not present in the serum indicates intrathecal IgG synthesis. CSF oligoclonal bands are present in the large majority of patients with MS, but are nonspecific and can be seen in CNS infections and other CNS inflammatory conditions. If oligoclonal bands are present in a patient with CIS, this does increase the risk of future development of MS, but not more so than MRI findings. Use of oligoclonal bands for diagnosis in MS has diminished with the advent of MRI criteria, but may be useful in cases of patients in whom the disease is suspected but clinical-radiologic criteria are not met. However, whether or not a patient with CIS and normal MRI who is found to have CSF oligoclonal bands should initiate treatment or just be followed with serial imaging is an individualized decision.

Visual Evoked Potentials

Visual evoked potentials (VEPs) examine a particular EEG of visual stimulation (P100) to evaluate conduction along the visual pathway. If the latency of P100 between the two eyes is significantly different, this suggests slowed conduction in one optic nerve, a sign of optic nerve dysfunction. In cases of possible MS, abnormal VEPs can suggest prior optic neuritis. The optic nerve can also be examined by optical coherence tomography to look for prior damage to the nerve.

Radiologically Isolated Syndrome

Occasionally, an MRI performed for another reason (e.g., headache) may demonstrate what appears to be a “textbook” appearance of MS, but the patient has had no clinical attacks and has a normal neurologic examination. This is called radiologically isolated syndrome (RIS). Such patients should be evaluated for other evidence of possible MS (e.g., spinal cord lesions on MRI, oligoclonal bands) and other causes of CNS white matter disease (e.g., systemic inflammatory disorders, cerebrovascular disease). However, this evaluation is commonly unremarkable. Even if ancillary laboratory or radiologic evidence suggestive of MS is discovered, it is unclear how this should be interpreted if the patient has no clinical history suggestive of demyelinating disease. Therefore, such patients are typically followed clinically and with serial imaging. About one third of patients with RIS will eventually develop MS and have presumably been discovered in the preclinical stage, while many appear never to develop any clinical features of the disease. As in patients with a clinically isolated syndrome, many practitioners initiate empiric vitamin D supplementation in patients with RIS.

Fulminant Demyelinating Disease

Rarely, fulminant demyelination can occur as a first attack of MS, in a patient with established MS, or as an isolated demyelinating phenomenon. Marburg variant MS, tumefactive demyelination, and Balo’s concentric sclerosis are names given to differing radiologic and pathologic appearances of these entities, which may be difficult to distinguish from tumor or other inflammatory condition of the CNS (e.g., CNS vasculitis, sarcoidosis, neuromyelitis optica). Biopsy is necessary for diagnosis. If steroids are ineffective in treating fulminant demyelination, patients may be treated with IVIg or plasma exchange. If these are ineffective, cyclophosphamide and/or rituximab may be considered.

Treatment of Multiple Sclerosis

Acute Treatment of Flares of Multiple Sclerosis

Acute attacks of demyelination are typically treated with a 3–5 day course of IV methyprednisolone. This treatment is utilized whether it is the first attack (clinically isolated syndrome) or if the attack occurs in a patient with known MS.

Long-term Treatment of Relapsing-Remitting MS

The goal of disease-modifying treatment for relapsing-remitting MS is to reduce the risk of flares and slow the progression of disability. The number of medications found to be effective toward these endpoints for relapsing-remitting MS continues to increase (Table 21–1). However, there are limited data to guide decision-making with respect to choices between agents or change from one therapy to another.

The agents in longest use for relapsing-remitting MS are the injectable treatments interferon beta and glatiramer acetate. Their long-term safety is well-established and the side effects are generally tolerable, so many practitioners use these as first-line agents. However, many practitioners now offer the option of an oral agent (teriflunomide, fingolimod, dimethyl fumarate) to patients with a new diagnosis of MS. Comparative efficacy is hard to gauge based on differing trial designs, but either injectables or oral agents are likely reasonable first-line options depending on a patient’s comorbidities. No therapy reduces the relapse rate to zero, so judging the success of therapy can be challenging since patients on any agent would still be expected to have relapses and development of new lesions on serial MRIs. If a patient is thought to have an unacceptable rate of relapse and/or significant increase in lesion burden on follow-up neuroimaging on one medication, change to another medication is often made.

Notable toxicities and adverse reactions of which to be aware include:

• Bradycardia and macular edema with fingolimod. Baseline electrocardiogram (ECG) and cardiac monitoring are required with the first dose (due to risk of first-dose bradycardia). Baseline ophthalmologic examination and subsequent periodic ophthalmologic monitoring are also necessary.

• Hepatotoxicity and teratogenicity of teriflunomide (pregnancy category X). Liver function monitoring is required, and women planning to conceive require elimination of teriflunomide with cholestyramine.

• Progressive multifocal leukoencephalopathy (PML) with natalizumab (and less commonly with fingolimod and dimethyl fumarate). PML is an opportunistic CNS viral infection caused by the JC virus (see “Viral Focal Brain Lesions” in Ch. 20). The risk of developing PML with natalizumab treatment is related to three factors:

  • Whether the patient has antibodies to the JC virus

  • Whether the patient has received prior immunosuppressive therapy

  • Length of treatment with natalizumab beyond 2 years

Any patient being considered for natalizumab treatment must be screened for serum JC virus antibodies. In patients who are not found to have JC virus antibodies, the risk of developing PML is exceedingly low (about 1 in 10,000 [0.01%] even after 2 years of treatment), and this risk remains low even if the patient has received prior immunosuppressive therapy (~2.5 in 10,000 [0.025%]) (Fox and Rudick, 2012). In patients who are JC virus antibody positive, risk of PML after 2 years of treatment increases about 40-fold to approximately 40 per 10,000 (0.4%), and with prior immunosuppression such a patient’s risk would nearly triple beyond that to over 100 per 10,000 (1%) (Fox and Rudick, 2012). Given these risks, JC virus antibody–negative patients on natalizumab therapy must be screened for JC virus antibody every 6 months to evaluate for seroconversion. If PML develops during natalizumab treatment, natalizumab is discontinued, and plasma exchange is used to remove natalizumab.

MS therapies should be discontinued prior to conception in women seeking to become pregnant (though some practitioners continue glatiramer acetate during pregnancy).

Treatment of Progressive Multiple Sclerosis

Evidence is limited and inconclusive for the optimal treatment of both primary progressive MS and secondary progressive MS, so treatment is largely supportive. However, some practitioners treat patients with progressive MS with rituximab, methotrexate, steroids, cyclophosphamide, or mitoxantrone (mitoxantrone is rarely used due to cardiac toxicity).

Symptomatic Management in Multiple Sclerosis

In addition to trying to modify the disease course of MS, many symptoms of MS can be effectively treated:

• Fatigue: amantadine, modafinil

• Gait: dalfampridine (contraindicated if seizures or renal failure)

• Spasticity: baclofen, tizanidine, botulinum toxin

• Bladder dysfunction: anticholinergics (e.g., oxybutynin), alpha-blockers (e.g., terazosin)

• Depression: psychiatric/psychological care, selective serotonin reuptake inhibitors (SSRIs)

Neuromyelitis optica (NMO or Devic’s disease) is a demyelinating disease of the CNS associated with an antibody against aquaporin-4. The disease predominantly affects the optic nerves and the spinal cord as the name suggests. These regions may be affected simultaneously at presentation or in sequential attacks on one or both optic nerves and the spinal cord. The myelitis is distinct from that seen in MS in that it is longitudinally extensive: usually longer than three spinal cord levels (Fig. 21–3).

Although the optic nerves and spinal cord are the main sites of involvement in NMO, lesions in the brain are common as well. These are less often symptomatic than in MS, and often differ in location and appearance compared to the classic locations in MS. Lesions in NMO may be found in the hypothalamus, around the fourth ventricle, and, in rare cases, may form large confluent lesions. Lesions around the fourth ventricle can cause hiccups, nausea, and/or vomiting, which may be the first presentation of the disease in some cases. Although women are more commonly affected than men (similar to MS), the geographic distribution in NMO is uniform (as opposed to the latitude gradient seen in MS). In patients of Asian and African origin, NMO may be more common than MS.

NMO-IgG (anti–aquaporin-4 antibody) is highly sensitive and specific for the disease. Serum NMO-IgG should be part of the evaluation of atypical white matter lesions in the brain, brainstem, and/or spinal cord, since the specificity of the antibody is expanding the spectrum of what is considered NMO (and may even be positive in patients with brain lesions who have neither myelitis nor optic neuritis).

Oligoclonal bands are less commonly present in NMO compared to MS. The CSF is usually inflammatory, and a lymphocytic pleocytosis is common.

When lupus or Sjögren’s syndrome causes a myelitis it also tends to be longitudinally extensive. The majority of patients with lupus or Sjögren’s syndrome who develop longitudinally extensive transverse myelitis are positive for NMO-IgG and appear to have NMO in addition to the underlying systemic autoimmune disease.

Acute attacks of NMO are treated with steroids. Plasma exchange or cyclophosphamide may be considered for fulminant attacks that do not respond to steroids. Long-term immunomodulatory therapy to reduce the risk of subsequent relapses is most commonly with rituximab, azathioprine, or mycophenolate mofetil.

A comparison of the features of MS and NMO is presented in Table 21–2.

Acute disseminated encephalomyelitis (ADEM) is a multifocal CNS demyelinating syndrome more common in children and young adults. ADEM can be thought of as the CNS analogue to Guillain-Barré syndrome in the peripheral nervous system: both are acute inflammatory conditions commonly preceded by infection or vaccination. Given the multifocal nature of brain lesions in ADEM, the patient can have multifocal neurologic deficits and/or an encephalopathy. The neuroimaging pattern consists of multifocal large T2 hyperintensities in the white matter that may have an incomplete ring of contrast enhancement (Fig. 21–4). CSF is inflammatory with elevated protein and a mild lymphocytic pleocytosis. CSF oligoclonal bands may be present, and do not necessarily predict future development of MS since they can be seen in isolated monophasic ADEM.

Treatment of ADEM is with IV steroids. IVIg or plasma exchange may be considered in severe cases that do not respond to steroids. Most patients recover entirely. Rarely, ADEM represents a fulminant first presentation of MS. Most patients undergo neuroimaging 6–12 months after presentation to evaluate for any new lesions to suggest the development of MS. The disease may continue to evolve radiographically over the first few months, and the emergence of new radiographic lesions in the short-term can still be seen in what ultimately turns out to be a monophasic course of the illness.

A fulminant hemorrhagic variant of ADEM known as Weston-Hurst syndrome can be fatal.

Optic neuritis is inflammation of the optic nerve. It presents with painful visual loss over days. It is most commonly unilateral, although it can occur bilaterally. The pain is typically worse when the patient moves the affected eye. On examination, decreased acuity, decreased color vision, and an afferent pupillary defect may be observed (see “Impaired Pupillary Constriction Due to a Lesion of Cranial Nerve 2” in Chapter 10). Although an inflamed optic nerve head on fundoscopy confirms the diagnosis in the appropriate clinical context, inflammation of the optic nerve may be retrobulbar with no visible abnormality of the optic nerve head itself. Optic nerve enhancement can often be seen on contrast-enhanced MRI of the orbit.

The time course of optic nerve dysfunction is key to the differential diagnosis: A more insidious progression of monocular visual loss may suggest a mass lesion (e.g., optic nerve glioma, optic nerve sheath meningioma), whereas a more acute presentation may suggest a vascular etiology (e.g., ischemic optic neuropathy) (see “Monocular Visual Loss” in Chapter 6).

Although optic neuritis is commonly associated with MS and NMO, other potential etiologies include:

• Systemic inflammatory disease (e.g., sarcoid, lupus)

• Infections (e.g., Bartonella, syphilis)

• Paraneoplastic optic neuritis (associated with antibodies against CRMP-5 [collapsing response mediator protein 5])

Most patients with optic neuritis recover significantly over the first 2–4 weeks, although continued recovery may occur over subsequent months. Treatment with IV steroids leads to quicker recovery but does not change the long-term outcome with respect to recovery of visual acuity.

Optic neuritis may be the first flare of MS. Overall, 15 years after an episode of optic neuritis, approximately half of patients will develop MS. The risk is strongly modulated by whether or not there are MRI lesions suggestive of MS at the time of optic neuritis. Patients with zero MRI lesions have a 15-year risk of 25% of developing MS, whereas patients with one or more MRI lesions have a 15-year risk of 72% of developing MS (Optic Neuritis Study Group, 2008). A patient with isolated optic neuritis who does not have MRI evidence of dissemination in space and time is an example of a clinically isolated syndrome, the management of which is discussed above.

If optic neuritis occurs sequentially in one optic nerve and then the other within a short period of time, NMO should be considered.

Transverse myelitis (TM) refers to inflammation of the spinal cord. Like optic neuritis, TM can occur as an isolated monophasic condition (i.e., idiopathic, infectious, or postinfectious), as a flare in a patient with MS or NMO (or as a clinically isolated syndrome), in the setting of systemic autoimmune disease (e.g., lupus, Sjögren’s syndrome, sarcoid), or as a paraneoplastic syndrome (antibodies are most commonly against CRMP5; see “Paraneoplastic Syndromes of the Nervous System” in Chapter 24). The presentation is one of a rapidly evolving myelopathy that leads to weakness and sensory changes in the extremities and bowel and/or bladder dysfunction. The clinical presentation may be symmetric or asymmetric depending on the extent of the lesion. Reflexes may be decreased or absent initially, but hyperreflexia typically emerges over time.

The differential diagnosis for myelitis is broad. If onset of myelopathic symptoms is sudden, vascular etiology (spinal infarct or hemorrhage) or acute spinal cord compression should be considered. Acute-onset myelopathy raises concern for epidural abscess or schistosomiasis (in endemic regions or in patients from them) (see “Infections of the Spine” in Chapter 20). A more subacute progression of myelopathic symptoms suggests malignancy, vascular malformation (e.g., dural arteriovenous fistula [see “Spinal Dural Arteriovenous Fistula” in Chapter 19]), cervical spondylosis, vitamin B12 or copper deficiency, radiation-induced myelopathy (see “Radiation Therapy-Induced Myelopathy” in Chapter 24), or indolent infection (e.g., vacuolar myelopathy of HIV/AIDS, HTLV-1, tuberculosis of the spine, syphilis, neurocysticercosis; see “Infections of the Spine” in Chapter 19). (See also “Causes of Myelopathy” in Chapter 5.)

The main localization-based differential diagnosis for transverse myelitis is Guillain-Barré syndrome (GBS) (see “Guillain-Barré syndrome” in Chapter 27), since both may cause hyporeflexia or areflexia in the acute setting (upper motor neuron signs take time to emerge after acute spinal cord insult). Bowel/bladder dysfunction is extremely uncommon in GBS, but is common in transverse myelitis. A spinal level to pinprick is common in transverse myelitis but would be atypical in GBS, although confluent sensory loss in GBS may make it difficult to determine if a spinal level is present. Continued progression of symptoms in the legs with no symptoms or signs in the arms would make a lumbar or thoracic spinal lesion more likely than GBS. An acute cervical myelopathy (e.g., cervical transverse myelitis or epidural abscess) may be harder to distinguish from GBS in the acute phase. MRI of the spine should be performed in any case of suspected myelopathy.

MRI in transverse myelitis will generally reveal a T2-hyperintense spinal cord lesion that may enhance. If the lesion is longitudinally extensive (>3 levels), evaluation for NMO, lupus, and Sjögren’s syndrome should be pursued.

Lumbar puncture in inflammatory transverse myelitis typically reveals a nonspecific inflammatory pattern: elevated protein and a mild pleocytosis (usually lymphocytic). A significant pleocytosis (>100 cells) should raise concern for an infectious myelitis.

If there is no antecedent history of infection or vaccination, the question emerges as to whether an episode of transverse myelitis represents the first flare of MS (i.e., a clinically isolated syndrome). As with optic neuritis, if there are brain MRI lesions suggestive of MS, the risk of conversion to MS is far higher than if there are no such lesions (80% vs approximately 10%) (Scott et al., 2011). Transverse myelitis associated with later conversion to MS is typically less severe, with spinal cord lesions that only partially transect the axial diameter of the cord rather than a full-thickness transverse lesion. Post-infectious or infectious myelitis and NMO are typically more severe and the lesions are typically more fully transverse. If oligoclonal bands are present in a patient with transverse myelitis, this is also predictive of later development of MS. As with optic neuritis and clinically isolated syndrome in general, decisions must be individualized about whether or not to begin treatment to reduce the risk of further flares when concern for MS is high in a patient with isolated transverse myelitis.

Treatment of immune-mediated/idiopathic transverse myelitis is with IV steroids. Plasma exchange may be considered in severe cases.