Patients With Infectious or Inflammatory Neuropsychiatric Impairment

Overview

While there has always been a close association between neurologic and psychiatric disorders, in the past decade, with the identification of a new class of autoimmune encephalitides that are associated with profound neuropsychiatric impairments, and the realization that psychiatric disorders, such as schizophrenia, may be linked with deficient components of the immune system that are responsible for synaptic pruning, the lines between the two disciplines are increasingly blurred. This overlap necessitates collaboration between neurologists and psychiatrists and an overall multidisciplinary approach to many shared patients. Similarly, there may be considerable overlap in the manifestations of infectious and inflammatory etiologies. The blending between “neurologic,” “psychiatric,” “infectious,” and “inflammatory” disorders can make the diagnosis and treatment of these disorders a daunting task. This chapter aims to demystify some of these complex disorders and to offer a practical approach to the diagnosis and treatment of infectious or inflammatory disorders that present with neuropsychiatric impairment.

Potential Etiologies of Acute and Sub-Acute Neuropsychiatric Impairment

Encephalitis Versus Encephalopathy

In the hospital setting, neuropsychiatric impairment is most often secondary to similar, but distinct entities—encephalitis and encephalopathy. In general, encephalitis , or an inflammation of the brain, can be thought of as being due to direct involvement of the brain parenchyma itself, while encephalopathy is more of a general clinical term that refers to a non-specific confusional state that is not necessarily due to malfunction or inflammation of the organ itself. For instance, encephalopathy can stem from the dysfunction of other organs, such as the liver in hepatitis, the kidneys in uremia, and the body as a whole, as in sepsis. Encephalitis can also result in encephalopathy, but the opposite is not necessarily true; i.e., encephalopathy does not necessarily imply encephalitis. Encephalitis is commonly encountered in the hospital setting. Unfortunately, in the majority of cases, exact causes remain unknown. Even in cases where there is a high suspicion of an infectious cause, the causative microbe often goes un-identified. In the future, this may change with the incorporation of next-generation sequencing, but this technology, which allows one to screen body fluids, including cerebrospinal fluid (CSF), for any known pathogen, is not widely available and is currently only available on a research basis. In recent years, it has become evident that many previously cryptogenic cases of encephalitis are autoimmune, mediated by pathogenic antibodies to neuronal cell surface antigens, such as N-methyl- d -aspartic acid receptors (NMDARs). Indeed, a retrospective analysis of nearly 500 cases of cryptogenic encephalitis demonstrated that about 1% of them were due to NMDAR encephalitis. The pathophysiology underlying these autoimmune encephalitides remains unknown.

Causes of Encephalopathy

Encephalopathy has a relatively broad differential diagnosis. High on that list are toxic (both endogenous and exogenous) and metabolic causes. Infectious causes include hepatitis, systemic infections, and especially in the elderly, more common infections (such as pneumonia and urinary tract infections). Inflammatory causes, such as autoimmune hepatitis, primary biliary sclerosis, lupus, and immunoglobulin (Ig) A nephropathy, lead to encephalopathy primarily by leading to end-organ dysfunction or failure. There is recent literature that suggests that even celiac disease can lead to psychosis. Encephalopathy typically manifests clinically as an altered mental status, or a delirium-type picture with waxing and waning confusion, disorientation, hallucinations, and sometimes seizures.

Work-Up for Encephalopathy

Blood and/or urine laboratory work-ups for encephalopathy commonly reveal abnormalities, such as metabolic or electrolyte derangements (for example hyponatremia, hypercalcemia, hypercapnia, hyperammonemia, transaminitis, elevated creatinine and/or blood urea nitrogen, hyper/hypoglycemia), elevated white blood cell count, and/or positive toxicology screening (positive drug screen and/or elevated anion gap). Electroencephalography (EEG) can reveal generalized triphasic discharges, which are classically seen in toxic/metabolic encephalopathy, or seizures. Brain magnetic resonance imaging (MRI) most often is normal or reveals symmetric changes, indicative of a generalized process that affects the brain. The work-up of altered mental status secondary to encephalopathy is not the focus of this chapter. The reader is referred to Chapter 10, Chapter 27, Chapter 28 . Rather, this chapter will focus upon infectious and inflammatory causes of encephalitis.

Encephalitic Neuropsychiatric Impairment

Clinical Features of Infectious Encephalitis

If encephalitis is suspected, distinguishing between infectious and inflammatory causes ( Table 22-1 ) can be challenging, as there is often overlap in patients' initial clinical presentations. For the purpose of this chapter, inflammatory causes of encephalitis refer to autoimmune neurologic disorders, including those associated with cancer, termed “paraneoplastic disorders.” In general, infectious causes of encephalitis are often associated with fevers, but this may not always be true, especially in immunocompromised or elderly patients, who may not be able to mount a strong immune response. If present, headaches are more often noted in infectious, as opposed to inflammatory encephalitis. Additionally, infectious encephalitis usually results in a precipitous decline over the course of hours to days, as opposed to the decline seen with inflammatory causes of encephalitis, which more typically manifest over the course of weeks to months. Of course, exceptions exist. The neuropsychiatric decline noted in syphilis can manifest decades after initial infection. Also, a rapid decline may not be as prevalent for immunocompromised individuals. For instance, while acquired immune deficiency syndrome (AIDS) dementia has long been recognized, it is becoming evident that more subtle cognitive deficits similar to mild cognitive impairment, often a precursor to Alzheimer's disease, appear to develop slowly in patients with human immunodeficiency virus (HIV) over time. This is true even for patients with what was thought to be relatively well-controlled HIV infection, as evidenced by low or undetectable serum viral loads. In recent years, it has become evident that even with well-controlled systemic disease, some patients with HIV infection may have progressive encephalitis, possibly due to “central escape” of the virus from medications that do not penetrate the CSF space well, or from persistent low-level central nervous system (CNS) inflammation.

TABLE 22-1

Clues to an Autoimmune Versus Infectious Etiology for Encephalitis

CLUES TO AN AUTOIMMUNE ETIOLOGY	CLUES TO AN INFECTIOUS ETIOLOGY
Symptoms: predominantly psychiatric (especially early and at an unusual age for initial presentation)	Symptoms: broader, including fever, ^a headache, obtundation, meningismus
Onset: subacute (days to weeks)	Onset: often precipitous ^a (hours to days)
Medical history: personal or family history of organ- or non-organ-specific autoimmune disorder	Medical history: immunocompromised state
Serum: systemic markers of autoimmunity (e.g., elevated ANA or TPO antibodies) and/or identification of a neural autoantibody	Serum: markedly elevated ^a ESR and/or CRP, tests (cultures, ELISAs, PCR, western blots, antibodies, blood smears) identifying specific microbes
Cancer status: history of or concurrent malignancy	Cancer status: generally N/A, unless immunocompromised (e.g., from chemotherapy)
CSF studies: elevated WBC (usually <100 cells/µL), protein (usually <100 mg/dL), IgG index, oligoclonal bands, synthesis rate, and/or identification of a neural autoantibody	CSF studies: elevated WBC (usually >100 cells/µL ^a ), protein (usually >100 mg/dL), elevated RBC and/or xanthochromia possible, decreased glucose, tests (cultures, ELISAs, PCR, western blots, antibodies, smears) identifying specific microbes
EEG: focal abnormalities	EEG: no particular pattern; could have triphasics
MRI brain: T2/FLAIR hyperintensities, rarely enhancement	MRI brain: T2/FLAIR hyperintensities (may be symmetric), more often has enhancement, may have leptomeningeal or spinal cord involvement, may have mass effect, may have blood
PET brain: areas of hyper/hypometabolism	PET brain: not typically done
Therapy: response to immunosuppression	Therapy: response to antimicrobials

ANA, antinuclear antibody; CRP, C-reactive protein; CSF, cerebrospinal fluid; EEG, electroencephalography; ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; FLAIR, fluid attenuation inversion recovery; IgG, immunoglobulin G; MRI, magnetic resonance imaging; N/A, not applicable; PCR, polymerase chain reaction; PET, positron emission tomography; RBC, red blood cell count; TPO, anti-thyroperoxidase antibody; WBC, white blood cell count.

a May not apply to immunocompromised patients.

In addition to encephalitis, infections can also trigger meningitis, or inflammation of the meninges, the protective coverings of the brain. Signs of meningismus include fever, headache, nuchal rigidity (which may produce positive Kernig's and Brudzinski's signs), and vomiting with or without photophobia. Meningitis is much less frequently associated with autoimmune causes.

Clinical Features of Autoimmune Encephalitis

Regardless of the specific manifestations, there are a few features that raise suspicion for autoimmune disorders. In general, there is a distinct change from a patient's baseline functional status over days to weeks. The patient's symptoms may have a fluctuating course. Family members often believe that the patient's behavioral or cognitive changes came “out of the blue” and are highly divergent from the patient's baseline personality. When considering psychiatric presentations, the patient's age is important; for example, it is highly unusual for hallucinations to occur in a young child and for schizophrenia to first manifest in a patient's 60s. Such circumstances would be less consistent with a primary psychiatric disorder and more consistent with autoimmune encephalitis. Additionally, a patient presenting primarily with isolated psychiatric symptoms is more likely to have an autoimmune disorder than an infectious encephalitis. Patients with autoimmune encephalitis may have a personal or family history of systemic autoimmune disease, such as Hashimoto's thyroiditis, rheumatoid arthritis, or celiac disease. Moreover, as with systemic autoimmunity, patients may have overlapping autoimmune neurologic diseases, such as neuromyelitis optica (NMO) and autoimmune encephalitis, making diagnosis particularly challenging. Paraneoplastic disorders cause neurologic symptoms in patients with malignancy, commonly before the cancer is diagnosed. A personal history of neoplasm in a patient with new neurologic symptoms should raise one's suspicion of a paraneoplastic disorder. However, especially early on into a patient's course, it can be difficult to differentiate infectious from inflammatory encephalitides, especially because many patients with autoimmune encephalitis present with a viral prodrome, as in up to half of cases of NMDAR encephalitis.

Work-Up for Infectious and Inflammatory Causes

Bloodwork

Initial work-up for infectious and autoimmune causes of encephalitis should always include basic bloodwork, urinalysis, and toxicology screens, to exclude readily diagnosed causes of encephalopathy. Serum markers that raise the suspicion of an infectious or inflammatory encephalitis include an elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP). In general, markedly elevated values are more often associated with infectious, as opposed to inflammatory encephalitides. In autoimmune encephalitis, while ESR and CRP values can be elevated, they can also be normal. In the work-up for autoimmune encephalitis, elevated antinuclear (ANA) or thyroid peroxidase (TPO) antibodies, although non-specific, can be considered as helpful markers for an autoimmune tendency in a patient. Specific infectious etiologies can be tested for in the serum, most often by growing cultures or testing for antibodies with enzyme-linked immunosorbent assays (ELISAs) or western blots or nucleic acids with polymerase chain reactions (PCRs). A blood smear may be useful for detecting organisms and/or abnormal blood cells. Testing should be chosen based on a patient's presentation and personal risk factors, taking into account their age, sex, medical history, location, behaviors, travel history, and immunocompromised status, if applicable. Consulting with an infectious diseases specialist, either general or neurologic, can be useful to determine the specific tests to order.

Neural Autoantibody Testing

The past decade has seen the identification of over 10 new neurally directed autoantibodies that have been linked with autoimmune encephalitides. Many of these are now available for commercial testing and are available as part of panels that are grouped by symptomatology, including encephalitis, seizures, and dementia, in addition to more traditional paraneoplastic panels. As there can be significant overlap in the clinical signs and symptoms associated with each neural autoantibody, it is prudent to order a comprehensive autoantibody evaluation, as opposed to testing for a single autoantibody or a small sub-set of them. Neural autoantibody testing is available for serum and CSF and it is important to analyze both of them, as they are not necessarily equivalent. For instance, some autoantibody tests, such as for voltage-gated calcium channel (VGCC) antibodies, have been validated only in serum. Additionally, testing for other antibodies, such as the aquaporin-4 antibodies associated with NMO, is more sensitive from the serum, as compared to NMDAR antibody testing, which is more sensitive from CSF. For example, an analysis of paired CSF and serum samples from 250 patients with NMDAR encephalitis showed that whereas all the CSF samples tested positive for NMDAR antibodies, between 6% and 13% (depending on the methodology used) of the corresponding paired serum samples tested negative for NMDAR antibodies. Thus, testing both the serum and the CSF raises the overall sensitivity (and specificity) of the testing. It is important to note that neural autoantibody testing is not fool-proof; sometimes it can reveal the presence of antibodies that are poorly correlated with the patient's symptoms and other times the patient may test positive for a low level of an antibody, such as low-level glutamic acid decarboxylase (GAD-65) autoantibodies, which may only indicate an autoimmune tendency, as opposed to a specific autoimmune encephalitis diagnosis. Thus, the results of neural autoantibody testing must be interpreted carefully to determine whether they are clinically relevant. Table 22-2 lists neural autoantibodies commonly associated with autoimmune encephalitides.

TABLE 22-2

Neural Autoantibodies Associated With Autoimmune Encephalitides

ANTIGEN	INTRACELLULAR/CELL SURFACE	CLINICAL FEATURES	TUMOR ASSOCIATION
AGNA (SOX1)	Intracellular	Lambert-Eaton myasthenic syndrome (LEMS), limbic encephalitis, neuropathy	Highly associated with small-cell lung cancer, especially with LEMS
AMPAR	Cell surface	Limbic encephalitis; may occur with pure psychiatric manifestations. Relapses common	~70% (lung, breast, thymoma)
Amphiphysin	Intracellular	Wide clinical spectrum: stiff person syndrome, cerebellar degeneration, limbic encephalitis, encephalomyelitis, myelopathy, peripheral neuropathy, opsoclonus myoclonus	~85% (breast, small-cell lung cancer)
ANNA-1 (Anti-Hu)	Intracellular	Wide clinical spectrum: sensory neuronopathy, limbic encephalitis, cranial neuropathies, cerebellar degeneration, encephalomyelitis, partial epilepsy, status epilepticus, autonomic dysfunction including intestinal pseudo-obstruction, opsoclonus myoclonus	~80% (small-cell lung cancer, neuroblastoma, prostate cancer)
CASPR2	Cell surface	Encephalopathy, Morvan's syndrome, neuromyotonia Relapses of encephalopathy common	~0–40% (thymoma)
CRMP-5 (anti-CV2)	Intracellular	Wide clinical spectrum: cerebellar degeneration, limbic encephalitis, optic neuritis, retinopathy, uveitis, chorea, encephalomyelitis, sensorimotor neuropathy	~75% (small cell lung cancer, thymoma)
DPPX	Cell surface	Encephalopathy with CNS hyperexcitability: confusion, psychiatric manifestations, tremor, myoclonus, nystagmus, hyperekplexia, PERM-like symptoms, ataxia Diarrhea and profound weight loss common	Rare B-cell neoplasms reported
GABA _a R	Cell surface	Prominent seizures, status epilepticus	Infrequent
GABA _B R	Cell surface	Limbic encephalitis, prominent seizures, status epilepticus	~50% (lung, neuroendocrine)
GFAP	Intracellular	Wide clinical spectrum: encephalopathy, tremor, headache, myelopathic signs, meningeal signs, optic disc edema, psychiatric symptoms, ataxia, autonomic dysfunction, seizures, meningoencephalomyelitis	~1/3 (teratoma ≫ adenoma, CNS glioma, lung cancer)
GAD-65	Intracellular	Wide clinical spectrum: encephalopathy, stiff person syndrome, cerebellar ataxia, seizure disorder With cancer more likely to see opsoclonus myoclonus syndrome and encephalomyelitis	~10% (lung cancer, neuroendocrine tumor, thymoma, breast cancer)
GlyαR	Cell surface	Wide clinical spectrum: stiff-person syndrome, PERM, limbic encephalitis, cerebellar degeneration, or optic neuritis	Infrequent
LGI-1	Cell surface	Limbic encephalitis, faciobrachial dystonic seizures, REM sleep behavior disorder, myoclonus ~60% with hyponatremia	≤10% (small-cell lung cancer, thymoma)
Anti-Ma2 (Ta)	Intracellular	Ma2 (only): limbic encephalitis, hypothalamic dysfunction, brainstem encephalitis	Germ-cell testicular cancer common
mGluR5	Cell surface	Ophelia syndrome: limbic encephalitis, myoclonus Very few cases	Hodgkin's lymphoma; may occur without tumor
NMDAR (GluN1)	Cell surface	NMDAR encephalitis: progression through psychiatric manifestations, insomnia, reduced verbal output, seizures, amnesia, movement disorders, catatonia, hypoventilation, autonomic instability, coma ~50% viral prodrome ~30% with “delta brush pattern” on EEG Relapses 12% at 2 years	Age-dependent: ~10–45%, most often ovarian teratomas, rarely carcinomas, rare in children
Neurexin-3α	Cell surface	Confusion, seizures, altered consciousness Often follows viral prodrome (fever, headache, GI symptoms) Patients can deteriorate rapidly Few cases reported	None reported
VGCC (N-type, P/Q type )	Cell surface	N: variable; includes encephalopathy, seizures P/Q: cerebellar degeneration, seizures	Sometimes associated with small-cell lung cancer
VGKC complex	Cell surface	Wide clinical spectrum: includes LGI-1 and CASPR2, but also dementia and pain syndromes	Variable, ≤10–40% (small-cell lung cancer, thymoma)

Percentage refers to percentage of patients with particular antibody that also have malignancy.

AGNA, antiglial nuclear antibody; AMPAR, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA, anti-neuronal nuclear antibody; CASPR2, contactin-associated protein-like 2; CNS, central nervous system; CRMP-5, collapsin response mediator protein 5; DPPX, dipeptidyl-peptidase-like protein-6; EEG, electroencephalography; GABAR, gamma-amino-butyric acid receptor; GAD-65, glutamic acid decarboxylase; GI, gastrointestinal; GluN1, ionotropic NMDA glutamate receptor 1; GlyαR, glycine alpha receptor; LEMS, Lambert-Eaton myasthenic syndrome; LGI-1, leucine-rich; glioma-inactivated 1; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartic acid receptor; PERM, progressive encephalomyelitis with rigidity and myoclonus; REM, rapid eye movement; SOX1, sex determining region Y box 1 transcription factor; VGCC, voltage-gated calcium channel; VGKC, voltage-gated potassium channel complex.

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