Check Your Diagnosis — Patient 32
Perry Jay Foreman, M.D., Ph.D.
Acute Disseminated Encephalomyelitis (Presumptive)
Patient #32 presented with evidence of subacute, progressive pyramidal dysfunction (asymmetrical lower extremity weakness, increased tone, and hyperactive DTRs), spinal cord involvement (incontinence and T6 sensory level), and cranial nerve dysfunction (diplopia and dysarthria). These findings imply a diffuse process involving the central nervous system. The lack of mental status changes implies primarily white matter disease, which was confirmed by MRI. The MRI showed patchy areas of increased T2-weighted signal primarily in the brainstem, but also involving the spinal cord and subcortical white matter; most of these lesions enhanced with contrast on T1-weighted scans, implying an active process with breakdown of the blood-brain barrier. CSF studies showed increased cell counts (initially PMN predominance) with elevated protein and decreased glucose levels. This suggests an active inflammatory process; but cultures were negative, implying a non-infectious etiology. The low glucose levels most likely resulted from the presence of inflammatory cells in the CSF (low glucose may be seen in infections of the CNS, inflammatory processes involving the CNS, and states of impaired glucose transport into the CSF). Together, these findings suggest active inflammation, resulting in demyelination within the CNS.
The differential diagnosis for diffuse white matter involvement in an adult is broad, including various infectious, inflammatory, and neoplastic processes. Included within the differential are fungal and mycobacterial disease (excluded by culture data), Lyme disease (essentially excluded by negative titers, the rare occurrence of this condition in this part of the country, and the absence of supportive history), and various unusual infections, such as Brucellosis, etc. (excluded by the absence of fever, culture data, and clinical story). CNS lymphoma may present with multifocal white matter involvement, but is unusual in the non-immunocompromised individual (CNS lymphoma typically occurs in a localized region in this population). Metastatic cancers would not have the MRI appearance suggestive of demyelination and would not present with the CSF findings in this case (unless the patient developed meningeal carcinomatosis).
The most likely possibility, then, is an inflammatory process affecting the neuraxis at several points (spinal cord, brainstem, and subcortical white matter). The differential diagnosis would then include CNS involvement from systemic lupus erythematosis (or other collagen vascular diseases), CNS vasculitis, sarcoidosis, or inflammatory demyelination following infection (post-infectious demyelinating encephalomyelitis) or associated with multiple sclerosis. The lack of historical or laboratory support for SLE, sarcoid, or other collagen vascular diseases essentially excludes these from consideration. The vigorous inflammatory response would be highly unusual for a CNS vasculitis, leaving the most likely possibility of primary CNS inflammation/demyelination.
Further dissection between acute disseminated encephalomyelitis and a first attack of multiple sclerosis is futile. By definition, this patient cannot be given a diagnosis of multiple sclerosis at this time (no separation of lesions in time); but it is impossible to determine whether or not this attack was the first evidence of MS, or simply a monophasic attack of CNS demyelination. The absence of a preceding viral illness is not unusual for acute disseminated encephalomyelitis, though its presence helps to confirm the diagnosis.
Absolute confirmation of the diagnosis would require brain biopsy. In this case, the patient improved to baseline after a trial of high dose intravenous steroids and has remained asymptomatic since; brain biopsy was therefore not indicated.
Acute disseminated encephalomyelitis (ADEM) is an autoimmune, monophasic, demyelinating disease generally associated with preceding viral infection and thought to be secondary to molecular mimicry and formation of T-cell and B-cell response to endogenous proteins in the myelin layer. Most cases begin within a few days of a preceding infection, but often there is no history of antecedent infection. Clinically, it is impossible to differentiate this entity from a first attack of multiple sclerosis, and the two may have a similar underlying pathophysiology. ADEM more closely mimics experimental autoimmune encephalomyelitis in that it is a monophasic illness as opposed to multiple sclerosis, which is polyphasic or progressive by definition.
Several infectious agents are thought to precede the development of ADEM, including: Measles (most common, 1/1000 measles cases, with autoreactive T-cells and antibodies to MBP), Rubella, Corona virus, Mycoplasma, influenza, parainfluenza, CMV, EBV, HHV-6, Varicella-chicken pox, and nonspecific URI's. Vaccines to smallpox, rabies (Semple vaccine), mumps, rubella, influenza and live measles have also been reported to antedate development of this condition. It is currently unclear why so many infectious agents would result in a similar process in susceptible individuals if molecular mimicry serves as the underlying cause of the condition. It may be that these various infections initiate immune responses within the CNS, or uncover myelin proteins not previously "seen" by the immune system, resulting in a vigorous inflammatory response.
The clinical course is highly variable, ranging from a slow progression over weeks to a fulminant course over hours to days. A clinical hallmark of the condition is its monophasic course, differentiating it from multiple sclerosis. Again, however, it is impossible to determine with a single attack whether or not the patient has simply experienced the first of many MS attacks.
Neurological signs and symptoms are variable and nonspecific, but evidence of upper motor neuron dysfunction is the rule. Headache, meningimus, and altered mental status with confusion progressing to lethargy and coma are common accompaniments. Cranial nerve involvement is common, particularly optic neuritis. Motor involvement ranges from focal spastic weakness to quadraplegia. Sensory findings are almost always present. Often there is evidence of transverse myelitis. Deep tendon reflexes may initially be decreased, but usually are increased with Babinski signs present. Cerebellar dysfunction is common and initially may be the only finding.
Laboratory evaluation typically shows a CSF pleocytosis with up to 150-200 WBCs, generally with a lymphocytic predominance. Rarely PMNs are predominant in the CSF (a finding that initially suggests meningitis rather than this diagnosis). The protein level is usually elevated, but generally not higher than 180 mg/dl.
Radiological evaluation is quite helpful. While the CT scan is generally normal, MRI images show multiple white matter lesions on T2 and flair sequences with gadolinium enhancement on T1. These findings are typical, but not diagnostic of, inflammatory demyelinating lesions, as seen with multiple sclerosis; but they are frequently more confluent and larger in size than typical MS plaques. Frequently the posterior fossa and spinal cord are involved, with uniform enhancement of lesions (suggesting active disease) unlike MS in which there often is patchy enhancement if multiple lesions are present.
Treatment is aimed at suppressing the immune response. Generally, high dose corticosteroids (e.g. I.V. Solumedrol 1g QD) are administered over 3-5 days. Plasma exchange and IV IG have been used with reported good benefit, but it is unclear if these therapies are more successful than steroid use. More aggressive immunosuppressive therapy with intravenous cytoxan is advocated by a few individuals, but there are no clear guidelines for its use. The decision to use steroids or chemotherapy is therefore empirical at this point.
The prognosis is variable. For milder cases, 90% of patients achieve completely recovery. In more severe cases, especially those following measles infection, mortality may be as high as 5-20%; and 50% of patients so afflicted are left with a permanent neurological disability.