What is the differential diagnosis for this patient? And what are the essential next steps?
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.
What is the differential diagnosis and what is the next step in management?
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