Diagnosis

The diagnosis of NMO, rather than MS, in a patient with a history of ON (Fig. 47-1) and myelitis is largely dependent on documentation of longitudinally extensive spinal cord lesions (more than three spinal segments). Such extensive intramedullary spinal cord lesions are unique to NMO in contrast to the very short segment MRI findings in MS (Fig. 47-2).

Figure 47-1 Optic Nerve Atrophy.

Figure 47-2 Neuromyelitis Optica.

A very specific NMO-IgG serum autoantibody is identified that binds to the central nervous system (CNS)–dominant water channel aquaporin-4, a structure that is normally present on astrocytes. This leads to the primary pathologic change, namely, loss of this aquaporin-4 water channel protein. This is occasionally associated with secondary demyelination. Hypothalamic and periventricular demyelination, the latter previously thought to be almost MS specific, are now also recognized to be associated with NMO-IgG/anti-AQP4 seropositivity. This particular distribution of lesions corresponds with the site of AQP4 expression within the brain. Preliminary experiments suggest that anti-AQP4 autoantibodies are pathogenic. This antibody has a high sensitivity and specificity for NMO being present in at least 75% of these cases; its presence now provides a specific diagnostic modality. This totally contrasts with MS, where there is nothing absolutely specific present to confirm that diagnosis.

Prognosis

When one is confronted with a new case of ON, the testing for NMO-related anti-AQP4 antibodies is very important diagnostically as well as prognostically. In this setting, the finding of this specific seropositivity predicts poor future visual outcome, and possibly rapid onset of NMO. In the converse, the patient presenting with longitudinally extensive transverse myelitis (LETM) and who is found to be antibody positive for the NMO antibody has more than a 50% chance of developing ON or recurrent severe ON within just 1 year. This is an important designation as NMO has a much worse prognosis than MS per se because the antibody-positive NMO patient does not respond to the usual immunomodulatory treatments that are often initially effective for MS.

Treatment

In contrast to MS where beta-interferon is often the therapy of choice for prevention of disease relapses, a few immunosuppressant medications are the treatment of choice for both NMO and relapsing optic neuritis (RON). Previously, before specific antibody testing had been available for a precise NMO diagnosis, classic clinical cases sometimes responded to very high doses of daily intravenous methylprednisolone.

Recently treatment with rituximab, a monoclonal antibody against CD20⁺ B cells, appears to reduce the frequency of attacks for NMO. It also appears to potentially stabilize or even lessen disability. This proved effective by decreasing the number of relapses as well as improving or at least stabilizing disability in 80% of previously medically refractive NMO patients in one recent multiinstitution trial. However, this is not a panacea as this medication has been associated with serious infectious complications, including progressive multifocal leukoencephalopathy (PML) and even death in a few patients. Currently these concerns are limiting the adoption of rituximab as the drug of choice for NMO. Unfortunately, previous experience with other chronic immunosuppressive agents, including azathioprine, cyclophosphamide, cyclosporine, methotrexate, mitoxantrone, and mycophenolate mofetil have proved disappointing. NMO patients taking these various drugs are found to continue to have relapses and progression of their disease.

Clinical Presentation

A severe focal or multifocal encephalopathy associated with pyramidal, cerebellar and brainstem signs is typically evidenced. Seizures occur with 25% of patients. An association with bilateral optic neuritis and transverse myelitis is particularly suggestive of a demyelinating disease such as ADEM. These various presentations reflect the disseminated CNS involvement.

Diagnostic Approach

MRI is the primary diagnostic methodology. Commonly one sees multifocal asymmetric gadolinium-enhancing lesions throughout the brain and spinal cord (Fig. 47-3). Typically these lesions have varied imaging patterns, including nodular, gyral, amorphous, spotty, and ringlike shapes. ADEM patients typically have MRI abnormalities seen at the cortical gray and subcortical white matter interface. This contrasts significantly with MS, where the periventricular white matter is most commonly involved.

Figure 47-3 Acute Disseminated Encephalomyelitis.

The cerebrospinal fluid (CSF) is abnormal in 70% of patients, showing a modest lymphocytosis, increased protein with 60% having oligoclonal bands, and normal glucose. Electroencephalography often shows diffuse slowing compatible with an encephalopathic process. Epileptiform spike discharges are unusual in ADEM.

Differential Diagnosis

This includes acute MS, various acute aseptic meningoencephalitides, vasculitides, and very rare metabolic leukoencephalopathies, such as Schilder disease or Leigh syndrome. Cerebral biopsy is often necessary to confirm an ADEM diagnosis, especially in adults and atypical cases. Perivenous mononuclear cell infiltration associated with demyelination within the cellular cuff is the typical finding in patients with ADEM (Fig. 47-2).

Therapy and Prognosis

Methylprednisolone, in very high doses. is the treatment of choice as most patients with ADEM improve with this modality. However, if that fails, intravenous immunoglobulins, plasmapheresis, or cytotoxic drugs are given. Acute disseminated encephalomyelitis is usually associated with a good prognosis. Most patients sustain mild residual deficits or even achieve complete recovery.

Clinical Presentation

Early symptoms of AHL include fever, headaches, and malaise. These rapidly progress to confusion, decreased level of consciousness (obtundation) and coma. Aphasia, hemiparesis, brainstem signs, and seizures are common focal signs.

Diagnosis

Peripheral leukocytosis is often present in AHL, with WBC counts as high as 40,000/mm³. The lesions on MRI are usually larger and have more edema than in ADEM. Hemorrhages are frequently seen. The CSF usually demonstrates polymorphonuclear pleocytosis, increased protein, and a normal glucose level. Although AHL is associated with petechiae, the number of RBCs can vary from none to thousands. Increased levels of CSF gamma globulins may be present.

Pathology

The pathologic findings in AHL are unique and show widespread edema in the white matter, ball and ring hemorrhages, perivascular exudates, and perivenous foci of microglial proliferation (Fig. 47-2). Areas of demyelination are seen around the vessels.

Treatment

Early and aggressive treatment of AHL patients with high-dose corticosteroids is indicated and may occasionally lead to an improved clinical outcome.