Overview

Definition

Encephalitis is an inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the brain parenchyma caused by an infection that is usually viral and presents as diffuse or focal neuropsychologic dysfunction.

Epidemiology

• True incidence unknown
• The most common causes are of viral infectious etiology. 
• HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2 is the most common cause of sporadic encephalitis in the Western world.
• Arboviruses are the most common causes of episodic encephalitis in the United States (require insect vector).
• West Nile virus West Nile Virus West Nile virus is an enveloped, positive-sense, single-stranded RNA virus of the genus Flavivirus. Birds are the primary hosts and the disease is most often transmitted by Culex mosquitoes. Most people infected with West Nile virus are asymptomatic. Some patients develop West Nile fever (a self-limited, febrile illness) and a very small proportion of patients develop West Nile neuroinvasive disease. West Nile Virus is the most common cause of proven encephalitis in the United States.
• Japanese encephalitis is the most common in Asian countries.
• Extreme age groups are at the highest risk and experience a severe illness. 
• High mortality rate: around 10%
• Cognitive and neurologic disabilities are observed in most survivors.

Classification

There are 2 main types of encephalitis: 

• Primary: 
  • Infection occurs directly in the brain tissue.
  • Infection can also be the reactivation of a dormant virus from a previous infection.  
• Postinfectious:
  • Also known as acute disseminated encephalomyelitis Acute disseminated encephalomyelitis Acute disseminated encephalomyelitis (ADEM) is an immune-mediated, inflammatory, monophasic, demyelinating condition that affects the white matter of the brain and spinal cord. As a rapidly progressive post-infectious encephalomyelitis, ADEM is characterized by demyelination in the brain and spinal cord. Acute Disseminated Encephalomyelitis (ADEM) ( ADEM ADEM Acute disseminated encephalomyelitis (ADEM) is an immune-mediated, inflammatory, monophasic, demyelinating condition that affects the white matter of the brain and spinal cord. As a rapidly progressive post-infectious encephalomyelitis, ADEM is characterized by demyelination in the brain and spinal cord. Acute Disseminated Encephalomyelitis (ADEM))
  • Infection occurs elsewhere in the body.
  • Neurons are spared, but there is evidence of perivascular inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and demyelination.
  • Likely immune-mediated disease

Etiology

Viral encephalitis is the most common form of encephalitis. Bacterial, fungal, and parasitic encephalitides are extremely rare.

Viral causes:

• HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-1 and HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-2
• Arboviruses (transmitted by mosquitoes):
  • Eastern equine virus
  • Western equine virus 
  • Venezuelan equine virus
  • St. Louis virus
  • West Nile virus West Nile Virus West Nile virus is an enveloped, positive-sense, single-stranded RNA virus of the genus Flavivirus. Birds are the primary hosts and the disease is most often transmitted by Culex mosquitoes. Most people infected with West Nile virus are asymptomatic. Some patients develop West Nile fever (a self-limited, febrile illness) and a very small proportion of patients develop West Nile neuroinvasive disease. West Nile Virus
• Varicella zoster virus (VZV)
• Epstein–Barr virus 
• Rabies virus Rabies Virus Rabies virus is a single-stranded, negative-sense RNA virus. This bullet-shaped virus belongs to the family Rhabdoviridae and the genus Lyssavirus. Rabies is a preventable disease most often transmitted to humans through the bite of an infected animal (e.g., bats, raccoons, skunks, and foxes). Rabies Virus 
• Japanese encephalitis virus
• Chikungunya virus Chikungunya Virus Chikungunya virus belongs to the Alphavirus genus and causes a viral infection characterized by fever and joint pain. The arthropod-borne (arbovirus) virus is transmitted by mosquitoes (commonly Aedes albopictus and Aedes aegypti). Chikungunya Virus   

Other causes:   

• Syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis 
• Mycoplasma Mycoplasma Mycoplasma is a species of pleomorphic bacteria that lack a cell wall, which makes them difficult to target with conventional antibiotics and causes them to not gram stain well. Mycoplasma bacteria commonly target the respiratory and urogenital epithelium. Mycoplasma pneumoniae (M. pneumoniae), the causative agent of atypical or "walking" pneumonia. Mycoplasma spp.
• Toxoplasma Toxoplasma Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis gondii 
• Autoimmune 

Risk factors:

• Immunocompromised or weak immune system 
• Extreme age groups: infants and older adults 
• Residence in areas infested with mosquitos and ticks

Pathophysiology and Clinical Presentation

Pathophysiology

Transmission:

• Inhalation of respiratory droplets from an infected person
• Contaminated food or drink 
• Insect bites, especially in areas infested with mosquitos and ticks 
• Reactivation of dormant virus in the trigeminal ganglia ( HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2)

Pathogenesis:

• The virus replicates outside the CNS and binds to specific receptors on cell membranes. 
• The virus spreads to the CNS through a hematogenous route or by retrograde neuronal dissemination. 
• Once inside the neurons, the virus disrupts normal function and causes perivascular congestion, hemorrhage, and a diffuse inflammatory response.
• Some viruses exhibit regional tropism (e.g., HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2 has predilection for medial and inferior temporal lobes).
• Primary encephalitis directly affects gray matter Gray matter Region of central nervous system that appears darker in color than the other type, white matter. It is composed of neuronal cell bodies; neuropil; glial cells and capillaries but few myelinated nerve fibers. Cerebral Cortex; postinfectious encephalitis causes widespread demyelination.

Clinical presentation

Adults/older children: 

• Drowsiness 
• Fever 
• Headache
• Seizures  
• Muscle and joint pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain 
• Fatigue 
• Confusion 
• Problems in speech or hearing 
• Paralysis of the face or certain parts of the body
• Exaggerated deep tendon reflexes

Infants: 

• A bulge in the fontanel 
• Nausea and vomiting 
• Stiff body 
• Irritability 
• Refusal to feed  

Distinguishing features (point toward a certain etiology):

• Parotitis in mumps Mumps Mumps is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. Mumps is typically a disease of childhood, which manifests initially with fever, muscle pain, headache, poor appetite, and a general feeling of malaise, and is classically followed by parotitis. Mumps Virus/Mumps 
• Grouped vesicular dermatomal rash in VZV
• Features common in West Nile virus West Nile Virus West Nile virus is an enveloped, positive-sense, single-stranded RNA virus of the genus Flavivirus. Birds are the primary hosts and the disease is most often transmitted by Culex mosquitoes. Most people infected with West Nile virus are asymptomatic. Some patients develop West Nile fever (a self-limited, febrile illness) and a very small proportion of patients develop West Nile neuroinvasive disease. West Nile Virus: 
  • Flaccid paralysis
  • Maculopapular rash
• Features common in rabies:
  • Hydrophobia
  • Pharyngeal spasms
  • Myoclonus
  • Hyperactivity 
• Features common in St. Louis virus:
  • Tremors in the eyelids 
  • Tremors in the tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue
  • Tremors in the lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue
  • Tremors in the extremities 
• Meningoencephalitis (when meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges are also inflamed):
  • Stiff neck
  • Photophobia

Diagnosis

History

• Geographic exposure
• Arthropod bite
• Animal bite
• Known history of HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2 infection

Imaging

• CT scan: mostly useful to rule out tumors
• MRI:
  • Test of choice
  • HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2 encephalitis often manifests in the temporal lobes.
  • West Nile encephalitis: basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia, thalamus Thalamus The thalamus is a large, ovoid structure in the dorsal part of the diencephalon that is located between the cerebral cortex and midbrain. It consists of several interconnected nuclei of grey matter separated by the laminae of white matter. The thalamus is the main conductor of information that passes between the cerebral cortex and the periphery, spinal cord, or brain stem. Thalamus, cerebellum Cerebellum The cerebellum, Latin for "little brain," is located in the posterior cranial fossa, dorsal to the pons and midbrain, and its principal role is in the coordination of movements. The cerebellum consists of 3 lobes on either side of its 2 hemispheres and is connected in the middle by the vermis. Cerebellum, brainstem, and temporal structures involved
  • Hydrocephalus would suggest nonviral etiologies.
  • Postinfectious encephalitis: multifocal white matter lesions

CSF analysis by lumbar puncture

• Could be normal
• Cell counts (elevated lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes; WBCs < 250/mm³ )
• Protein (mild elevation; < 150 mg/dL)
• Glucose (normal or moderately reduced)
• CSF culture: viral culture not reliable
• CSF PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) testing (largely replaced by culture): 
  • HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-1, HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-2
  • Enteroviruses
  • VZV
  • CMV

EEG

EEG is abnormal in acute encephalitis.

Blood tests

• WBC count with differential
• A blood culture may be done to rule out a bacterial cause (in cases of meningoencephalitis).
• Additional testing is considered on the basis of the clinical presentation and exposure history:
  • Serology for the arboviruses
  • HIV testing

Management

Immediate response to encephalitis is crucial because it can quickly progress to complications.

Management

• Supportive therapy: 
  • Careful respiratory and cardiovascular monitoring 
  • Administration of IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids to maintain hydration and provide hemodynamic support 
  • Anti-inflammatory medication: corticosteroids (benefit unproven)
  • Mannitol to lower intracranial pressure (benefit unproven in viral encephalitis)
  • Anticonvulsants: phenytoin
• Antiviral therapy: 
  • Acyclovir: 
    • Empiric treatment for suspected HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2 encephalitis 
    • Should be started immediately to decrease morbidity and mortality
  • Ganciclovir 
  • Foscarnet 
• Postencephalitis therapy: 
  • Physiotherapy to improve strength and mobility 
  • Occupational therapy to aid in daily activities 
  • Speech therapy 
  • Psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy to improve behavioral health sequelae

Complications

• Complications are common in survivors and depend on:
  • Age of the individual affected 
  • Duration of the illness 
  • Immune status of the individual 
  • Etiology of infection 
• Complications that can occur:
  • Memory loss 
  • Muscle weakness and deterioration in coordination 
  • Change in personality 
  • Paralysis 
  • Loss of vision or hearing 
  • Speech impairment 
  • Epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy 
  • Difficulty breathing  
  • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma

Differential Diagnosis

• Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis: inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges usually caused by a bacterial or viral infection: Clinically, meningitis presents with headache, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and nuchal rigidity. Diagnosis is by clinical presentation, CSF analysis, and blood workup. Management (antimicrobials) depends on the etiology, but supportive treatment in all cases of meningitis is similar.
• Subarachnoid hemorrhage Subarachnoid Hemorrhage Subarachnoid hemorrhage (SAH) is a type of cerebrovascular accident (stroke) resulting from intracranial hemorrhage into the subarachnoid space between the arachnoid and the pia mater layers of the meninges surrounding the brain. Most SAHs originate from a saccular aneurysm in the circle of Willis but may also occur as a result of trauma, uncontrolled hypertension, vasculitis, anticoagulant use, or stimulant use. Subarachnoid Hemorrhage (SAH): bleeding within the subarachnoid space that occurs spontaneously or following head trauma Head trauma Head trauma occurs when external forces are directed to the skull and brain structures, resulting in damage to the skull, brain, and intracranial structures. Head injuries can be classified as open (penetrating) or closed (blunt), and primary (from the initial trauma) or secondary (indirect brain injury), and range from mild to severe and life-threatening. Head Trauma: Subarachnoid hemorrhage Subarachnoid Hemorrhage Subarachnoid hemorrhage (SAH) is a type of cerebrovascular accident (stroke) resulting from intracranial hemorrhage into the subarachnoid space between the arachnoid and the pia mater layers of the meninges surrounding the brain. Most SAHs originate from a saccular aneurysm in the circle of Willis but may also occur as a result of trauma, uncontrolled hypertension, vasculitis, anticoagulant use, or stimulant use. Subarachnoid Hemorrhage (SAH) presents with neck and shoulder pain Shoulder Pain Acute shoulder injuries are a common reason for visits to primary care physicians and EDs. Common acute shoulder injuries include acromioclavicular joint injuries, clavicle fractures, glenohumeral dislocations, proximal humerus fractures, and rotator cuff tears. Acute Shoulder Pain, numbness throughout the body, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, confusion and irritability, diplopia, and sudden headache. Diagnosis is by history, signs and symptoms, imaging, and cerebral angiography. Subarachnoid hemorrhage Subarachnoid Hemorrhage Subarachnoid hemorrhage (SAH) is a type of cerebrovascular accident (stroke) resulting from intracranial hemorrhage into the subarachnoid space between the arachnoid and the pia mater layers of the meninges surrounding the brain. Most SAHs originate from a saccular aneurysm in the circle of Willis but may also occur as a result of trauma, uncontrolled hypertension, vasculitis, anticoagulant use, or stimulant use. Subarachnoid Hemorrhage (SAH) is managed surgically. Antihypertensive agents are recommended.
• Subdural empyema: collection of pus between the dura mater and the arachnoid mater: Subdural empyema presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, lethargy, focal neurologic deficits, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. Diagnosis is by imaging, the most common being contrast-enhanced MRI. Management is surgical and with antibiotics.
• Brain abscess Brain abscess Brain abscess is a life-threatening condition that involves the collection of pus in the brain parenchyma caused by infection from bacteria, fungi, parasites, or protozoa. The most common presentation is headache, fever with chills, seizures, and neurological deficits. Brain Abscess: collection of pus in response to an infection or trauma that presents clinically with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, nausea, and vomiting: Diagnosis is by evaluation of signs and symptoms, blood tests, and imaging. Management includes antibiotic therapy and surgery to drain the abscess. 
• Stroke: damage to the brain due to interrupted blood supply: Stroke presents with difficulty walking, facial paralysis, blurred vision, slurred speech, and paresthesia. Diagnosis is by history and imaging. Management depends on the type of stroke. 
• Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia: condition in which blood glucose levels are lower than normal: Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia is an emergency condition that presents with rapid heart rate, tremors, diaphoresis, confusion, blurred vision, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. Diagnosis is by signs and symptoms and blood glucose levels. Management depends on the severity. Severe hypoglycemia is treated by IV glucose and/or glucagon injection.
• Delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium tremens: severe form of ethanol withdrawal that presents clinically with global confusion, agitation, hallucinations, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and diaphoresis: Diagnosis is by history and signs and symptoms. Management is with supportive therapy, benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines, and thiamine.