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

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  Multiple sclerosis (MS)

  
  
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  Neuromyelitis optica (NMO)

  
  
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  Acute disseminated encephalomyelitis (ADEM)

  
  
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  Optic neuritis

  
  
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  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:

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

  
  
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  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.

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

  
  
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  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):

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  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.

  
  
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  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.