Classification of demyelinating disease
The oligodendrocyte–myelin unit subserves saltatory conduction of the nerve impulse in the healthy central nervous system. Several disease processes compromise the structure and function of myelinated axons. Many result from inflammation and autoimmunity (see Chapter 7 for discussion of glial neurobiology and neuroimmunology).
Demyelination is the usual explanantion for episodic neurological symptoms and signs suggesting damage to white matter tracts of the optic nerves, brainstem, or spinal cord when this occurs in young people. Neurologists will also consider this explanation in older patients presenting with progressive symptoms implicating these same pathways, even when there is no suggestive past history. Both in its typical and atypical forms, multiple sclerosis is the most common demyelinating disease. This can usually be distinguished from rarer forms of demyelinating disease, but since our understanding of the cause, pathogenesis, and features of each remains incomplete, the present classification of demyelinating disease integrates aetiological, clinical, pathological, and laboratory components (Table 29.1).
However, we anticipate that a major part of future studies in multiple sclerosis will be to resolve further the question of disease heterogeneity, leading to a new taxonomy based on mechanisms rather than clinical empiricism. But at present, the variable ages of onset, clinical course, and protean manifestations, and the non-specific laboratory investigations continue to make demyelinating disease one of the more challenging diagnostic areas in neurology.
Table 29.1. The classification of demyelinating disease
1 Isolated demyelinating syndromes
- Acute haemorrhagic leucoencephalomyelitis—Hurst's disease
- Acute disseminated encephalomyelitis
- Optic neuritis
- Cord lesions
- acute necrotizing myelitis
- transverse myelitis
- chronic progressive myelopathy
- radiation myelopathy
- HTLV-I associated myelopathy
- Monophasic isolated demyelination—site unspecified
2 Multiple sclerosis
- Relapsing remitting
- Secondary progressive
- Primary progressive
- Malignant or Marburg variant
- Silent multiple sclerosis
- Devic's disease
- Balo's concentric sclerosis
- Combined central and peripheral demyelination
3 Central pontine myelinolysis
- Schilder's disease
- myelinoclastic diffuse sclerosis
- transitional diffuse sclerosis
- Globoid cell (Krabbe's disease) leucodystrophy
- X-linked childhood adrenoleucodystrophy
- X-linked adult onset adrenomyeloneuronopathy
- autosomal recessive neonatal adrenoleucodystrophy
- autosomal recessive Zellweger's syndrome
- Metachromatic leucodystrophy
- late infantile
- multiple sulphatase deficiency
- Pelizaeus Merzbacher disease
- connatal form
- late onset
- Adult-onset leucodystrophies
Pathologically, a simple approach is to distinguish those disorders of myelinated pathways associated with perivascular inflammatory cell infiltration from the non-inflammatory forms of demyelination. Inflammation initially characterizes the focal and multifocal lesions associated with demyelination in optic neuritis, transverse myelitis, multiple sclerosis, acute haemorrhagic (Hurst's disease) and acute disseminated encephalomyelitis, subacute necrotizing myelitis, transverse myelitis, and acute bilateral optic neuritis. Some other conditions, which have at times been separated, are now more often considered within the general context of multiple sclerosis; these include Balo's concentric demyelination, neuromyelitis optica (Devic's disease), Marburg-type hyperacute demyelination, and mixed peripheral and central forms of demyelination.
In some young patients with progressive neurological disease, there is widespread demyelination arising from genetically determined disorders of myelin formation. These leucodystrophies are characterized by extensive non-inflammatory confluent areas of demyelination. Because myelin is structurally abnormal in these conditions, they are often referred to as dysmyelinating disorders. The most common leucodystrophies encountered in paediatric and adult neurological clinical practice are metachromatic leucodystrophy, adrenoleucodystrophy, and Krabbe's disease. As new leucodystrophies are described, and diagnostic acumen and precision improve, many individuals previously classifed as having diffuse sclerosis can now be diagnosed more accurately. However, a proportion of childhood and adult-onset white-matter diseases cannot be classified biochemically, and remain in the heterogeneous group of diffuse sclerosis, also known as Schilder's disease.
Magnetic resonance studies have established the important point (not easily gathered from neuropathological studies) that single patches of demyelination rarely occur. It is now clear that many patients apparently having clinically isolated episodes of demyelination do, in fact, have widespread lesions. Later, they show a high conversion rate to clinically definite multiple sclerosis. The areas of white-matter damage in patients with leucodystrophy can be imaged and appear as diffuse confluent areas of abnormality in the cerebral white matter. These are usually quite distinct from the widespread discrete periventricular lesions seen in multiple sclerosis and other inflammatory demyelinating disorders. Although conventional magnetic resonance protocols do not reliably depict separate components of the pathological process in demyelinating disease, the distribution and appearance of lesions in multiple sclerosis, acute disseminated encephalomyelitis, primary progressive inflammatory demyelination, the leucodystrophies, and central pontine myelinolysis can usually be distinguished.
It is now well recognized that patients developing clinical evidence for extensive brainstem damage in the context of electrolyte imbalance, or following its correction, may develop large areas of pontine myelinolysis. These are not common conditions, but under the heading of central pontine myelinolysis should also be considered the even rarer cases of extrapontine myelinolysis and Marchiafava–Bignami disease, consisting of callosal demyelination associated with injudicious consumption of Italian red wine—a condition faithfully listed in textbooks but never knowingly encountered by their authors (this one included).