The constellation of fever, generalized weakness, and bulbar dysfunction can be from a multitude of diseases. Grouping them according to location of disease is useful in choosing diagnostic tests that are needed. Infectious etiologies for central nervous system (CNS) dysfunction (ie, meningitis, encephalitis, cerebral abscess) are important to diagnose and treat quickly. Given the emergent necessity of treating infectious etiologies of meningitis and/or encephalitis, it is prudent to begin treatment with antiviral and antibacterial agents while diagnostic testing proceeds. Intravenous (IV) acyclovir should be strongly considered as well as IV medication to treat bacterial meningitis, tuberculosis, and fungal infections, depending on clinical suspicion. Diagnosis and treatment of infectious diseases are discussed in Chapter 8, CNS Infection. To diagnose CNS infection, a lumbar puncture should not be delayed.

Although unlikely in this case, perhaps the most time-sensitive diagnosis would be a vascular etiology. In a patient with vascular risk factors and cranial nerve signs and symptoms, a posterior circulation ischemic event is most important to diagnose quickly. Although a noncontrast head CT is effective in diagnosing intracerebral hemorrhages, in this setting it is probably not very helpful. Magnetic resonance imaging (MRI) of the brain is the most effective tool for diagnosing ischemic strokes and also will help in diagnosing other diseases.

Once infectious and vascular etiologies are addressed, one must consider inflammatory diseases. The history of symptoms occurring after a viral prodrome, malaise, and low-grade fever is suggestive of a postinfectious inflammatory process. Acute disseminated encephalomyelitis (ADEM) is a disease that can cause rapid mental status changes and multifocal neurologic deficits. An MRI with and without gadolinium is necessary to diagnose ADEM.

Other possible parenchymal diseases include metastatic disease, post-radiation necrosis, posterior reversible encephalopathy syndrome (PRES), and other autoimmune inflammatory diseases such as tumefactive multiple sclerosis (MS) and central nervous system (CNS) manifestations of systemic autoimmune diseases: lupus, Behçet syndrome, vasculitis, and paraneoplastic diseases.

Leptomeningeal processes can cause encephalopathy and multifocal neurologic symptoms. Again, infectious processes are the most urgent to diagnose. Other possibilities are inflammatory diseases such as sarcoidosis, neoplasms, and carcinomatous meningitis.

Although the patient’s encephalopathy suggests otherwise, another important location of disease can be in the peripheral nervous system. Demyelinating diseases such as Guillain-Barré syndrome (GBS) can progress over days and impair bulbar function. In fact, some diseases can affect both the central and peripheral nervous systems to produce this clinical syndrome. Bickerstaff encephalitis, a variant of GBS, involves ophthalmoplegia, ataxia, areflexia, and encephalopathy. It is associated with peripheral motor axonal demyelination with brainstem encephalitis. The detection of the antiganglioside immunoglobulin G (IgG) GQ1b antibody is helpful in the diagnosis of this disease.¹ In a recent case series of patients with ADEM, 43% had polyradiculoneuropathy, mostly demyelinating.² If there is clinical suspicion for peripheral involvement, electromyography (EMG) and nerve conduction studies (NCSs) are warranted. Patterns seen on EMG and NCS are discussed in Chapter 6, Neuromuscular Diseases.

The patient underwent a lumbar puncture that showed white blood cells (WBCs), 10 000 cells/μL; 0 red blood cells (RBCs); lymphocytes, 67%; monophils, 33%; glucose, 65 mg/dL; protein, 80 g/dL; albumin index, 11.4 (elevated); herpes simplex virus (HSV) polymerase chain reaction (PCR), negative; no detected oligoclonal bands; bacterial cultures, negative; encephalitis panel negative; and paraneoplastic panel, negative.

The MRI showed multiple bilateral lesions in the white matter of both hemispheres and large lesions affecting the basal ganglia and thalamus with minimal mass effect (Figure 10-1), which suggested a multifocal disease process affecting mostly white matter and deep gray matter.

ADEM is typically, if not always, a monophasic syndrome characterized by multifocal white matter demyelination. The typical clinical description of ADEM includes a rapid onset of progressive encephalopathy associated with multifocal neurologic deficits. The clinical syndrome is usually preceded by an antecedent infection or vaccination. A prodromal phase with fever, headache, and malaise may precede the full clinical syndrome.³ Although more commonly seen in the pediatric population, it is also encountered in adults. Its pathology of perivenous “sleeves” of inflammation and demyelination recently has been discovered and explored.⁴ The most commonly used definition has been published by the International Pediatric MS Study Group: ADEM—“A first clinical event with a polysymptomatic encephalopathy, with acute or subacute onset, showing focal or multifocal hyperintense lesions predominantly affecting the CNS white matter without evidence of previous destructive white matter changes and no history of a previous clinical episode with features of a demyelinating event… .”³

MRI findings of ADEM have been extensively characterized. Lesions are typically large, multiple, and asymmetric and involve subcortical and central white matter, located at the gray-white junction in the hemispheres, cerebellum, and brainstem. Gadolinium enhancement is variable. Patterns can be complete ring enhancing, nodular, gyral, or spotty. As opposed to multiple sclerosis, the deep gray matter can be involved, especially the caudate head, globus pallidus, putamen, and thalamus. Four types of lesions have been described: (1) small lesions (< 5 mm), (2) large, confluent, or tumefactive lesions, with edema and mass effect, (3) additional symmetric bithalamic involvements, and (4) acute hemorrhagic encephalomyelitis.^3-7

In this patient, cerebrospinal fluid (CSF) analysis showed no evidence of an infectious process. A mild pleocytosis and an elevated protein level with no oligoclonal bands are characteristic of ADEM.^3,7,8

Another possibility is progressive multifocal leukoencephalopathy (PML). PML is a disease that is multifocal and involves mostly the white matter. As our patient is human immunodeficiency virus (HIV)-negative and has no history of immune suppression, PML would be exceedingly unusual. CSF testing for the presence of the John Cunningham (JC) virus is helpful with the diagnosis.⁹

No randomized clinical trials exist to guide our management for patients with ADEM. Most treatment options are extensions from experience with other demyelinating, autoimmune diseases. IV methylprednisolone, 1 g/d for 3 to 5 days is the typical treatment of choice. The response to steroids can be dramatic, but up to one-third of patients may not respond. Patients with aggressive forms of ADEM may be less likely to respond to steroid treatment.^10,11

Aggressive ADEM with disease progression to the point of respiratory failure and admission to the NeuroICU is infrequent, occurring in < 20% of ADEM cases.^7,12 As the complications of mechanical ventilation and immobility compound with time, the speed of recovery needs to be emphasized, which argues for an aggressive treatment strategy.

Immune-modulating treatments, IV immune globulin (IVIG), and plasmapheresis (PE) are the next steps in management. IVIG has been used more widely. The usual dose of 0.4 g/kg/d for 5 days has been shown to be efficacious in case series. Improvement usually begins within a week and progresses until 2 months.^10-13 Although the mechanism for the efficacy for IVIG is not fully understood, it is thought to work by blocking the Fc receptor on macrophages and effectively decreasing the cell-mediated immune response.^14-16 In addition to direct immune effects, it may work by helping to normalize the blood-brain barrier.¹⁷ Some have debated that in cases of severe disease with peripheral nerve involvement, IVIG along with IV steroids should be first-line therapy.¹⁸

PE has also been used in ADEM, and a number of case reports support its use. PE is thought to work by removing humoral factors and affecting the balance of B cells and T helper type 1 and type 2 cells.^15,19 In a randomized study of PE in patients with acute CNS inflammatory demyelinating disease, PE was associated with improved neurologic recovery.²⁰ Other case studies also support the use of PE in CNS demyelinating disease and specifically in ADEM patients. In general, about half of patients will respond. Factors associated with improvement are early treatment and male gender.^21,22

If a patient does not improve after the first intervention regardless of whether IVIG or PE was performed, the other intervention in addition should be considered. Although no substantial evidence supports treatment with both PE and IVIG, some have suggested that it is more effective.^11,15

In fact, for patients in the NeuroICU who are severely affected, IV steroids should be started immediately. If little or no clinical response is observed in the first several days, PE should be started for a total of five to seven sessions. If the patient is still critically ill, IVIG should be instituted. PE treatment should be attempted first because of the evidence of efficacy in CNS demyelinating disorders as opposed to the limited evidence behind IVIG. A secondary advantage of treating with PE first is the theoretical advantage of first removing humeral factors through PE and subsequently adding IVIG. Although IVIG is technically easier, if PE is added as a second agent, PE will wash out the previously administered IVIG. If no response to steroids is seen in the first several days of treatment, escalation to immune-modulating therapy should occur quickly, as PE and IVIG are more effective the sooner they are started in the time course of the disease.

Other immune-modifying treatments including cyclophosphamide, interferon beta, glatiramer acetate, and rituximab have been suggested, but to date no large series of ADEM patients undergoing these treatments have been described. Owing to the rarity and refractory nature of ADEM in these patients, efficacy may be difficult to assess. Although treated with IV methylprednisolone sodium succinate (Solu-Medrol) for 5 days, PE, and IVIG, this patient did not clinically improve. The MRI with diffusion tensor imaging showed atrophy of white matter tract across time (Figure 10-2).