# 12 - SECTION 3 Nervous System Dysfunction

## SECTION 3 Nervous System Dysfunction

ANTIBIOTICS AND ANTITUBERCULOUS THERAPY
Antibiotic or antituberculous therapy may irrevocably diminish the 
ability to culture bacteria. However, hemodynamic instability or 
neutropenia is a good indication for empirical antibiotic therapy. 
If the TST or IGRA is positive, or if granulomatous disease is pres­
ent with anergy and sarcoidosis seems unlikely, or in any patient 
coming from an endemic region with a clinical picture fitting 
extrapulmonary tuberculosis, a trial of antituberculous therapy 
may be started, but not before mycobacterial cultures and, if avail­
able, mycobacterial PCR testing have been performed on material 
collected from the suspected location of inflammation. Especially 
in miliary tuberculosis, it may be very difficult to obtain a rapid 
diagnosis. If the fever does not respond after 6 weeks of empirical 
antituberculous treatment, another diagnosis should be considered. 
COLCHICINE, NONSTEROIDAL ANTI-INFLAMMATORY 
DRUGS, AND GLUCOCORTICOIDS
If the fever persists and the source remains elusive after comple­
tion of investigations, supportive treatment with acetaminophen 
or nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful. 
The response of Still’s disease to NSAIDs is dramatic in some cases. 
Colchicine is highly effective in preventing attacks of familial Medi­
terranean fever (FMF) but is not always effective once an attack is 
underway. When FMF is suspected, the response to colchicine is not 
a completely reliable diagnostic tool in the acute phase, but within 
weeks to months of continuous colchicine treatment, most patients 
show remarkable improvements in the frequency and severity of 
subsequent febrile episodes. Therefore, colchicine may be tried in 
patients with features compatible with FMF, especially when these 
patients originate from a high-prevalence region. In patients suffer­
ing from pericarditis as one of the main associated symptoms, col­
chicine may also be effective to prevent recurrent attacks. If Behçet’s 
disease is considered likely, colchicine may also have favorable effect.
The effects of glucocorticoids on giant cell arteritis and polymy­
algia rheumatica are impressive. Early empirical trials with gluco­
corticoids, however, decrease the chances of reaching a diagnosis 
for which more specific, less morbid, and sometimes life-saving 
treatment might be more appropriate, such as malignant lym­
phoma. The ability of glucocorticoids to mask fever while permitting 
the spread of infection or lymphoma dictates that their use should 
be avoided unless infectious diseases and malignant lymphoma 
have been sufficiently ruled out and inflammatory disease is prob­
able and is likely to be debilitating or threatening. 
INTERLEUKIN-1 INHIBITION
Interleukin (IL) 1 is a key cytokine in local and systemic inflammation 
and the febrile response. The availability of specific IL-1-targeting 
agents has revealed a pathologic role of IL-1-mediated inflamma­
tion in a growing list of diseases. Anakinra, a recombinant form 
of the naturally occurring IL-1 receptor antagonist (IL-1Ra), blocks 
the activity of both IL-1α and IL-1β. Anakinra is extremely effec­
tive in the treatment of many autoinflammatory syndromes, such 
as FMF, cryopyrin-associated periodic syndrome, tumor necrosis 
factor receptor–associated periodic syndrome, mevalonate kinase 
deficiency (hyper-IgD syndrome), Schnitzler’s syndrome, and Still’s 
disease. There are many other chronic inflammatory disorders in 
which anti-IL-1 therapy is highly effective. A therapeutic trial with 
anakinra can be considered in patients whose FUO has not been 
diagnosed after later-stage diagnostic tests and show signs of IL1-driven inflammation, such as serositis, elevated CRP, and elevated 
ferritin. When autoinflammation is considered in the differential 
diagnosis, IL-1 inhibition is preferred over corticosteroids to pre­
vent the metabolic, immunologic, and gastrointestinal side effects 
of glucocorticoid administration, and because IL-1 inhibition has 
superior efficacy.
■
■PROGNOSIS
The prognosis of patients with FUO mostly depends on the underly­
ing disease. In patients in whom FUO remains unexplained despite 

extensive evaluation, the prognosis is favorable. The risk of FUO-related 
mortality is probably highest during the early phases of the diagnostic 
process: in a cohort study including 168 patients without a final diag­
nosis, all four patients who died did so during the index admission; in 
two of them, diagnoses were made upon autopsy (intravascular lym­
phoma and bilateral pneumonia).

Large cohort studies in patients remaining without a diagnosis 
report high percentages of spontaneous resolution of fever and a mor­
tality of 8% or less during several years of follow-up. 18F-FDG-PET/CT 
may be helpful to predict which patients will resolve because normal 
18F-FDG-PET/CT scans are associated with higher rates of spontane­
ous resolution.
Syncope
CHAPTER 23
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■FURTHER READING
Betrains A et al: update on imaging in fever and inflammation of 
unknown origin: Focus on infectious disorders. Clin Microbiol Infect 
18:S1198, 2023.
Erdem H et al: Classical fever of unknown origin in 21 countries with 
different economic development: An international ID-IRI study. Eur 
J Clin Microbiol Infect Dis 42:387, 2023.
Mulders-Manders C et al: Fever of unknown origin. Clin Med 
15:280, 2015.
van Rijsewijk N et al: Molecular imaging of fever of unknown origin: 
An update. Semin Nucl Med 53:4, 2023.
Wright WF et al: Fever of unknown origin (FUO): A call for new research 
standards and updated clinical management. Am J Med 135:173, 2022.
Section 3	 Nervous System Dysfunction
Roy Freeman, Satish R. Raj

Syncope
Syncope is a transient, self-limited loss of consciousness due to acute 
global impairment of cerebral blood flow. The onset is rapid, dura­
tion brief, and recovery spontaneous and complete. Other causes of 
transient loss of consciousness need to be distinguished from syncope; 
these include seizures, vertebrobasilar ischemia, hypoxemia, and hypo­
glycemia. A syncopal prodrome (presyncope) is common, although loss 
of consciousness may occur without any warning symptoms. Typical 
presyncopal symptoms include lightheadedness or faintness, dizziness, 
weakness, fatigue, and visual and auditory disturbances. The causes of 
syncope can be divided into three general categories: (1) neurally medi­
ated syncope (also called reflex or vasovagal syncope), (2) orthostatic 
hypotension, and (3) cardiac syncope.
Neurally mediated syncope comprises a heterogeneous group of 
disorders that are characterized by a transient change in the reflexes 
responsible for maintaining cardiovascular homeostasis. Episodic 
vasodilation (or loss of vasoconstrictor tone), decreased cardiac output, 
and bradycardia occur in varying combinations, resulting in tempo­
rary failure of blood pressure control. In contrast, in patients with 
orthostatic hypotension due to autonomic failure, these cardiovascular 
homeostatic reflexes are chronically impaired. Cardiac syncope may be 
due to arrhythmias or structural cardiac diseases that cause a decrease 
in cardiac output. The clinical features, underlying pathophysiologic 
mechanisms, therapeutic interventions, and prognoses differ markedly 
among these three causes.
■
■EPIDEMIOLOGY AND NATURAL HISTORY
Syncope is a common presenting problem, accounting for ~3% of all 
emergency department (ED) visits and 1% of all hospital admissions. 
The annual cost for syncope-related hospitalization in the United States