Other demyelinating diseases: inflammatory and compressive

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Other demyelinating diseases

inflammatory and compressive

Neuromyelitis optica, acute disseminated encephalomyelitis, and acute hemorrhagic leukoencephalopathy are covered in this chapter, together with a group of diseases in which demyelination is probably caused by compression. Demyelinating diseases that occur in other clinical contexts are included in the relevant chapters: progressive multifocal leukoencephalopathy in Chapter 14, central pontine myelinolysis and multifocal necrotizing leukoencephalopathy in Chapter 22, and Marchiafava Bignami disease in Chapter 25. The leukoencephalopathies associated with lysosomal and peroxisomal disorders are covered in Chapter 23.

NEUROMYELITIS OPTICA (DéVIC’S DISEASE)

Neuromyelitis optica (NMO) is characterized by the development of optic neuritis and acute transverse myelitis within weeks of each other (Table 20.1). Approximately two-thirds of patients present with visual loss and subsequently develop paraplegia, sensory loss, and loss of bladder and bowel control, but in the remaining third the order may be reversed. Unlike remissions in MS, recovery in NMO is usually incomplete, even from initial attacks. Some patients die during or soon after the acute syndrome, but others, although severely incapacitated, survive for many years.

Table 20.1

Criteria for diagnosis of neuromyelitis optica

Optic neuritis

Acute myelitis

At least two of the following three supportive criteria:

1. Contiguous spinal cord MRI lesion extending over ≥3 vertebral segments

2. Brain MRI not meeting diagnostic criteria for MS

3. NMO-Ig seropositive status (i.e. serum contains for aquaporin-4 antibodies)

Adapted from Wingerchuk DM, Lennon VA, Pittock SJ, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006; 66:1485–1489.

MACROSCOPIC APPEARANCES

The optic nerves and affected region of the spinal cord are swollen and congested in patients who die during or soon after the acute presentation. The cord may appear necrotic on sectioning (Fig. 20.1). In patients who survive longer, the optic nerves become thin and gray-brown in color, while the cord shows similar discoloration (Fig. 20.2) and may be atrophic.

20.1 Acute neuromyelitis optica. Extensive softening of the spinal white matter and necrosis of the gray matter can be seen. The thoracic region (center section) is most severely affected.

20.2 Neuromyelitis optica. Brown discoloration of the upper part of the cervical cord in long-term survivor of neuromyelitis optica.

AQUAPORIN-4 ANTIBODIES AND NMO-SPECTRUM DISORDERS

The aquaporin-4 (AQP4) protein is a channel that controls the passage of water across the plasmalemma of certain types of cell. In the CNS, it is highly expressed in astrocytic endfeet around blood vessels and in circumventricular organs (e.g. the subforniceal organ and area postrema), and in certain subpopulations of ependymal cells (e.g. those covering the subforniceal organ).

Within these cells, AQP4 is complexed with the Na+-dependent excitatory amino acid transporter 2 (EAAT2); loss of AQP4 in NMO is associated with loss of EAAT2 as well.

AQP4-specific IgG is detectable in the serum of 60–90% of patients with NMO.

AQP4 autoimmunity is also found in a spectrum of CNS inflammatory demyelinating disorders (NMO-spectrum disorders) in patients who do not fulfil current criteria for a diagnosis of NMO but may have AQP4 antibody-associated foci of demyelination in the brain, particularly in AQP4-rich regions (e.g. the hypothalamus and periaqueductal region).

The prevalence of AQP4 autoimmunity is increased in patients with several other autoimmune diseases, such as myasthenia gravis, Graves disease, Hashimoto’s thyroiditis, systemic lupus erythematosus, and Sjögren syndrome).

MICROSCOPIC APPEARANCES

The optic nerves and spinal cord show extensive demyelination (Fig. 20.3). In the acute phase, involved segments of the spinal cord and optic nerve are inflamed, and the cord in particular may be partly necrotic (Fig. 20.4); the inflammatory infiltrates include perivascular neutrophils and eosinophils, and relatively few T cells. There tends to be pronounced perivascular deposition of immunoglobulins (particularly IgM) and C9neo (activated complement), and hyaline fibrosis of small blood vessels. Immunohistochemistry can also be used to demonstrate loss of AQP4 and EEAT2 in the demyelinated regions. The lesions become cavitated and gliotic in those patients who survive the acute stage, and there is usually associated degeneration of ascending and descending tracts.

20.3 Neuromyelitis optica. (a) Extensive demyelination of the optic chiasm, and (b)spinal cord.

20.4 Spinal white matter in acute neuromyelitis optica.
(a) This shows demyelinated spinal white matter largely replaced by sheets of foamy macrophages. (b) A few surviving axons are demonstrable by silver impregnation. (c) Scattered eosinophils (arrows) are present in some lesions. (d) Immunohistochemistry reveals perivascular deposition of IgM around many small blood vessels in the spinal cord in this example of acute neuromyelitis optica. (e) Hyaline thickening of many of the small blood vessels (arrows) within the demyelinated spinal cord.

Plaques of demyelination may also be present elsewhere in the CNS, particularly (but not exclusively) in NMO-rich hypothalamic and periaqueductal regions.

ACUTE DISSEMINATED ENCEPHALOMYELITIS

Preceding infections

The most commonly implicated preceding viral infections are measles, mumps, chickenpox (varicella), German measles (rubella), influenza, and infectious mononucleosis (caused by Epstein–Barr virus).

Other implicated preceding infections include Mycoplasma pneumoniae, Campylobacter jejuni, and group A streptococcal infections.

Symptoms of previous infection are not reported in all cases, and are often mild and non-specific.

Preceding vaccinations

The best documented implicated preceding vaccinations are smallpox vaccination and the use of a rabies vaccine contaminated by neural tissue, which are now largely of historic interest.

ADEM has been reported as a rare complication of influenza vaccination.

Although chronic neurologic disease has occurred after whooping cough (pertussis) vaccination, in most cases this is due not to ADEM but to cerebral hypoxic injury complicating seizures.

Iatrogenic

There are very occasional reports of ADEM in patients receiving sicca-cell preparations, gold, levamisole in combination with 5-fluorouracil, and levamisole alone.

ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM)

This is a multifocal inflammatory disorder of the CNS with a variety of synonyms, including perivenous encephalomyelitis and postinfectious encephalomyelitis. It is usually preceded by a systemic viral infection or, more rarely, vaccination and is believed to be due to a T cell-mediated hypersensitivity reaction. It resembles experimental allergic encephalitis induced in animals by immunization with any of several myelin antigens. Although some vaccination-related cases are attributable to contamination of the vaccines by neural tissue and amino acid homologies have been identified between certain viruses and myelin proteins, in most cases the cause of ADEM is not known.

ACUTE DISSEMINATED ENCEPHALOMYELITIS

The latent period between the preceding infectious illness (or vaccination) and the development of neurologic symptoms is usually a few days, but may be up to 3 weeks.

Typical manifestations include sudden headache, vomiting, and fever, with subsequent rapid development of weakness, sensory loss, ataxia, visual impairment, incontinence, and stupor. Seizures may occur. Symptoms of spinal cord involvement may predominate.

The symptoms and signs usually resolve over several weeks, allowing a good recovery in most patients. The recovery may be accelerated by administration of corticosteroids or, possibly, by plasmapheresis. Some patients are left with permanent neurologic deficits and approximately 20% die during the acute illness.

Relapses occur in 5–10% of cases (multiphasic disseminated encephalomyelitis; MDEM). A recurrent form of demyelinating perivenous encephalomyelitis has been reported in association with familial erythrophagocytic lymphohistiocytosis.

Very rarely, ADEM is associated with the development of concurrent Guillain–Barré syndrome (acute inflammatory demyelinating peripheral neuropathy).

MACROSCOPIC APPEARANCES

Apart from some congestion and swelling, the brain and spinal cord may look macroscopically normal. In some cases, scattered small foci of yellow or gray discoloration, some obviously centered on a small blood vessel, are evident in the white matter (Fig. 20.5). The gray matter may also be involved, although usually to a lesser degree.

20.5 Macroscopic appearance of brain in ADEM.
(a) Congested blood vessels in the white matter are surrounded by ill-defined zones of gray discoloration. These are most prominent in the left cerebral hemisphere. (b) The deep parietal white matter and corpus callosum have a mottled appearance due to the gray perivascular discoloration.

MICROSCOPIC APPEARANCES

Many small veins and venules within the brain parenchyma are surrounded by an infiltrate of lymphocytes, macrophages, and occasional plasma cells. The inflammatory infiltrate extends a variable distance into the surrounding tissue and is associated with a corresponding zone of demyelination (Fig. 20.6). There may be small perivascular hemorrhages. Although loss of myelin predominates, there may be some axonal destruction. Arteries are relatively free of inflammation (Fig. 20.6), but there are often inflammatory cells in the leptomeninges. Subpial inflammation and demyelination may occur in the brain stem and spinal cord.

20.6 Histology of ADEM.
(a) Infiltrate of lymphocytes and macrophages around a vein (v) in the cerebral white matter. Note the paucity of inflammation in relation to the adjacent artery. (b) A zone of demyelination surrounds the affected blood vessels. (c)Because the demyelination is so closely related to veins and venules, it tends to form a more irregular pattern than is usually seen in multiple sclerosis. (d) A combined solochrome cyanin stain for myelin and neurofilament immunostain for axons reveals a perivascular sleeve of (brown) axons that lack a (blue) myelin sheath (arrows). (e) Slightly larger zone of perivenular demyelination.

ACUTE HEMORRHAGIC LEUKOENCEPHALOPATHY

Like ADEM, AHL may be preceded by a systemic viral or respiratory infection such as measles or primary atypical pneumonia (caused by M. pneumoniae).

AHL has also been described in ulcerative colitis and Crohn’s disease, in the context of septicemia associated with immune complex deposition, in methanol poisoning, and as a reaction to the treatment of trypanosomiasis with melarsoprol, which contains an organic arsenic compound.

ACUTE HEMORRHAGIC LEUKOENCEPHALOPATHY

Patients present with headache, pyrexia, vomiting, drowsiness, and generalized weakness, proceeding rapidly to coma.

Seizures may be a prominent feature.

AHL is usually fatal within days.

ACUTE HEMORRHAGIC LEUKOENCEPHALOPATHY (AHL)

This fulminant, usually fatal, disorder, also known as acute hemorrhagic leukoencephalitis, is regarded by some as a hyperacute form of ADEM.

MACROSCOPIC APPEARANCES

The brain is soft and swollen. Sectioning reveals numerous small and occasional larger foci of hemorrhage, which are most prominent in the cerebral and cerebellar white matter and in the pons (Fig. 20.7).

20.7 Macroscopic appearance of brain in AHL.
Section through the cerebrum (a) and the cerebellum and pons (b)of a patient with Crohn’s disease who developed AHL. Perivascular hemorrhages and foci of gray-brown discoloration are scattered throughout the white matter in the cerebrum, and the brain stem and cerebellum. (Courtesy of Dr DA Hilton, Derriford Hospital, Plymouth, UK.)

DIFFERENTIAL DIAGNOSIS OF AHL

Fibrinoid necrosis and widely scattered hemorrhages may also be seen in:

fat embolism

thrombotic thrombocytopenic purpura

disseminated intravascular coagulation.

MICROSCOPIC APPEARANCES

Many small blood vessels undergo fibrinoid necrosis and are surrounded by a narrow zone of necrotic tissue containing nuclear debris and, in some cases, a larger zone of hemorrhage (Fig. 20.8). The classic description is of ring- and ball-shaped perivascular hemorrhages. Other blood vessels are still recognizable as veins or venules, but are surrounded by fibrin and a mixed inflammatory infiltrate, including neutrophils and mononuclear cells. Some fibers within the infiltrates are demyelinated, but others show axonal fragmentation (Fig. 20.9).