Fellows training with CNND faculty members actively engage with the intersections of basic science, clinical research, and the care of patients with neuroimmunological and neuroinfectious diseases.

Seay Fellowship in Neuropharmacology

This position is for post-graduate training for careers in neuroimmunology or neuroinfectious diseases, supporting research and clinical experience enhancing a career dedicated to these scientific areas. Candidates will craft experiences that may include clinical and/or basic research and mentoring. The fellowship is a one year fellowship that may be extended for up to three years.

Candidates should apply to Dr. Clifford.


Neuroimmunology Fellowships

Through the Department of Neurology’s Neuroimmunology Section, we offer two different types of postdoctoral fellowships, one fosusing on basic research (usually laboratory-based research), and the other equipping the fellow for a career in clinical trials. The goal of each is to provide clinical training and research opportunities to selected neurologists and PhD scientists to equip them for a career in neuroimmunology. The duration is typically two to three years.


Pediatric Neuroimmunology Fellowship

This yearlong fellowship provides training in pediatric MS and other demyelinating diseases, as well the autoimmune diseases of the CNS. In addition to clinical experience, the fellow will gain expertise in the science and pathophysiology of diagnosis and management of those disease conditions which represent the spectrum of this novel and underserved neurologic subspecialty.


Training experience

Fellows collaborate with CNND faculty to gain clinical and research experience in diseases including:

Autoimmune neurological diseases

write up about autoimmune encephalitis, myelitis, and the like. There are opportunities to work on these. – [Dr S Richard Dunham has a teaching clinic in this, and Dr Ances also has an established interest in this..]

About anti-NMDA receptor (NMDAR) encephalitis

Although anti-NMDA receptor (NMDAR) encephalitis remains a new diagnosis (first reported in 2007), a review of historical literature suggests that this distinct antibody-mediated cause of encephalopathy may have been previously captured under other diagnostic labels (e.g., “demonic possession”, “post-infectious encephalopathy”, “viral encephalitis NOS”). To date, well over 1000 cases are detailed across hundreds of published studies, contributing to a rapidly-expanding understanding of the clinical spectrum, associated risk factors, and available treatments.

As we now understand it, NMDAR encephalitis arises when autoantibodies against synaptic NMDARs disrupt neuronal signaling within the brain. Early clinical symptoms include hallucinations, delusions, and changes in mood. As antibody levels rise, worsening encephalopathy, seizures and the development of abnormal movements may be seen. In the most severe cases, NMDAR encephalitis may result in profound autonomic instability, compromising respirations and cardiac function. The isolation of IgG-class NMDAR autoantibodies from the blood or (preferably) cerebrospinal fluid of patients with a compatible clinical presentation establishes the diagnosis. Neuroimaging is normal in the majority of patients presenting acutely. Electroencephalogram (EEG) may show epileptiform activity, or more commonly, non-specific findings compatible with generalized encephalopathy.

Early descriptions of NMDAR encephalitis focused on disease in women of childbearing with an associated ovarian teratoma. Accordingly, NMDAR encephalitis was initially presumed to be a paraneoplastic disease. In the intervening decade, however, it has become increasingly clear that NMDAR encephalitis affects men and women (with a 1:8 male:female ration) of all ages, and may occur in the absence of tumors–particularly in patients <10 years of age.

The established association between NMDAR encephalitis and ovarian teratomas strongly implicates tumors in disease pathogenesis. This statement is supported by histopathological analyses reporting co-localized central nervous system tissue (including NMDAR) and lymphoid follicles within disease-associated tumors. Less is known concerning disease pathogenesis in patients without tumors. However, the high prevalence of viral prodrome (reported in upwards of 70% of patients), seasonal predilection of diseases (with peak incidence in spring and fall), and description of diseases following herpes simplex-and varicella zoster-mediated encephalitis, suggests that viral infection and/or immune-activation may contribute to NMDAR autoantibody formation.

Once the diagnosis is established, a thorough search for disease-associated tumors should be conducted, with special attention directed to imaging of the adnexal structures in the female patient. If a tumor is identified it should be promptly removed. Additional treatments emphasize the early administration of corticosteroids or intravenous immunoglobulin (“first line” therapies). therapeutic plasma exchange may also be considered. As many as 50% of patients show a robust response with gradual resolution of symptoms and signs within 4 weeks of initiation of first line therapies. The remainder of patients may require “second line” treatment with rituximab or cyclophosphamide. Shorter times to diagnosis and treatment are linked to better overall outcomes, and lower risks of relapse (currently estimated to occur in 14-25% of cases). While overall outcomes are good, cognitive challenges are increasingly recognized in survivors. This emergent finding represents an area of future research, working towards the ultimate goal of improving acute and long-term outcomes in patients with NMDAR encephalitis.

About rabies

Rabies is transmitted to humans through the saliva of infected dogs, bats, raccoons and foxes. The incubation period can be long, up to seven years, with a median of two months.

Risk factors

In the approach to the patient with encephalitis it is especially important to get a good history of the following exposures:

  • Travel history: travel to endemic areas, e.g.. China and JEV, United States or Europe in the summer months for WNV, Eastern Equine encephalitis on the East Coast.
  • Mosquito or tick exposure.
  • Exposure to wild animals– dogs, rodents, bats. In the case of bats or other wild animals there is usually known human-animal contact in which case the risk for rabies needs to be assessed.
  • Seasonality: Summer months for WNV, Ehrlichia in endemic areas.
  • Activities: camping (insect exposure), swimming (free living amebas, enterovirus), sexual contact (HIV).
  • Immunocompromised: VZV, CMV, JC virus.
  • Recent vaccination: ADEM.
  • Primary HSV infection in those <18 yo.
  • Ingestion of unpasteurized milk or other diary products (Listeria), raw meat (Toxoplasma).

Diagnosis of viral encephalitis

Clinical presentation

Regardless the etiology, encephalitis most commonly presents with fever, altered consciousness, behavioral changes, headache, seizures and/or focal neurological signs. In most cases it may be difficult to differentiate from meningitis, though usually, in encephalitis the altered mentation precedes the other symptoms. Meningeal signs such as those discussed in the acute meningitis section, may be present.

History

Presence of any of the risk factors should be assessed to aid in the presumptive diagnosis. A history of recent herpes outbreak may not be present, which should not lead against HSV-1 encephalitis. HSV-1 should always be considered in a patient who presents with a picture consistent with meningoencephalitis and any history of temporal lobe involvement. The patient may not be able to provide a history so if unable to obtain any information immediate action should be taken for diagnosis and management.

Physical examination

Fever, altered mental status are the most common findings while meningismus is usually absent. Focal neurologic signs, including aphasia and personality changes, ataxia, cranial nerve palsies may be present. Generalized or focal seizures may be present. Movement disorders may suggest a flavivirus infection such as WNV or JEV, although these may also be due to postinfectious syndromes such as ADEM or post streptococcal chorea (Sydenham’s chores). Look for other clues to guide etiology: erythematous rash (WNV, enterovirus), vesicular rash (HSV, VZV), oral or genital lesions, presence of animal or arthropod bites.

Diagnostic criteria

The key for the diagnosis of encephalitis is a high level of suspicion what will prompt a good history, physical exam and diagnostic procedures such as a lumbar puncture for CSF analysis and imaging.

  • Magnetic resonance imaging (MRI) is the most sensitive neuroimaging study in patients with encephalitis. If MRI is unavailable or contraindicated then a CT should be obtained with and without contrast. Findings may include temporal involvement (HSV-1), hemorrhages (VZV), white matter enhancement (JC virus), or periventricular lesions (CMV).
  • All patients with a suspicion of encephalitis should undergo a lumbar puncture unless contraindicated. The most common finding is a mild to moderate pleocytosis with lymphocytic predominance. Glucose is typically normal while protein is usually elevated. In HSV-1 encephalitis, CSF may be normal earlier in the course, so a normal CSFin a patient with a history suggestive of HSV encephalitis should not delay treatment and specific testing. Nucleic acid amplification tests (eg. PCR) are available for the following etiologies:
    • HSV-1 and HSV-2: HSV PCR should be sent in all patients with encephalitis. The sensitivity of HSV PCR os 98% and specificity 96%, although this varies according to the laboratory. It should be noted, that it may be negative on days one or two of the disease, so if negative, and clinical or imaging clues suggest HSV it should be repeated later in the course.
    • Enterovirus, adenovirus, influenza
    • JC
    • EBV
    • CMV
    • VZV
    • Ehrlichia
    • Bartonella, Mycoplasma
  • The diagnosis of WNV is made by presence of IgM in the CSF early in the course or in the serum after days 4-5. There is cross-reactivity with other flavivirus, such as St. Louis Encephalitis Virus or Japanese Encephalitis Virus so as discussed above risk factors and epidemiology need to be taken into account with a positive result. CSF antibodies should also be sent if rabies is suspected, as well as serologies.
  • Rabies is usually a postmortem diagnosis. If clinically indicated, diagnosis can also be made by rabies PCR from saliva or a nape biopsy.

Treatment

At present the only viral encephalitis which has treatment is HSV encephalitis. The treatment of choice is intravenous acyclovir at 10 mg/kg every 8 hours for 14-21 days. Given the high morbidity and mortality of Herpes Simplex Encephalitis (HSE) acyclovir should be started empirically on every patient who presents with a picture consistent of encephalitis. It has been shown that this will not affect the result of the HSV PCR test. An immediate response to acyclovir should not be expected, so if the clinical suspicion is high or if HSV PCR in CSF is positive, acyclovir should be continued even if patient fails to improve. If untreated, mortality due to HSE can be as high as 70%. However, even with treatment, HSE has high morbidity (up to 28%) and most survivors have some type of sequelae including severe cognitive impairment and disability.

Prevention

Only few viral causes of encephalitis can be prevented by immunization. These include rabies, poliomyelitis, JEV. In most cases, the best way to prevent would be to avoid exposures as mentioned above. Rabies vaccine as well as rabies immunoglobulin should be administered to anyone who has been bitten by a wild animal or unimmunized dog, or who has had an exposure to bats even without evidence of bite. (for CDC recommendations see: www.cdc.gov/rabies/exposure). There is a JEV vaccine approved for travelers to endemic areas. For information, visit the CDC website.

About viral encaphalitis

The term encephalitis refers to an inflammation of the brain parenchyma. As such, it usually presents with abnormalities of brain function, such as altered mentation or personality changes. On presentation it may be difficult to distinguish from acute meningitis, or in many cases the presentation has features of both entities, since they can occur together, in which case it is referred to as meningoencephalitis.

Etiologies

Most infectious encephalitides are of viral origin, though the etiology remains unknown in a large proportion of the patients. The most common cause of sporadic encephalitis worldwide is Herpes Simplex Virus, which has a high morbidity and mortality if untreated. Viral etiologies also depend on the epidemiology, the region of the world, time of the year and exposures. In the United States, West Nile Virus has emerged as a common cause, followed by enterovirus. Rabies is a fatal yet preventable cause of encephalitis. JC virus causes Progressive Multiple Leukoencephalopathy, described in immunosuppressed patients, especially those with HIV infection, on steroids or other immunosuppressant medications, and patients with sarcoidosis. Varicella zoster virus (VZV) can cause an acute encephalitis either as a complication of chicken pox (primary infection) or disseminated herpes zoster episode, particularly in the immunosuppressed. CMV is also a cause of encephalitis particularly in HIV and solid or bone marrow transplant patients. EBV, as well as adenovirus, are less common etiologies of encephalitis but are described and need to keep in differential.

Pathophysiology

The cardinal pathological feature is inflammation of the brain parenchyma. Inflammation is required to clear the pathogen. Depending on the etiologic agent, the damage may be caused by direct pathogen invasion or by an immune-mediated mechanism causing CNS damage, including demyelination and vasculitis:

  • Herpes simplex encephalitis — The most common herpes encephalitis in adults is HSV-1. The exact mechanism of invasion is unknown but is believed to be a direct invasion from the trigeminal or olfactory nerve. In approximately one third of the patients this follows an acute oropharyngeal infection; in another third it occurs following a reactivation or recurrent HSV-1 infection and in approximately one third it can occur as a reactivation within the CNS without a known primary or recurrent HSV-1 infection.
  • Arboviral encephalitis — In the United States, the most common arboviral infection is West Nile Virus which has emerged in the last 20 years. Worldwide, other arboviral infections to consider are Japanese Encephalitis Virus, (Southeast Asia, China), Chikungunya (India, sub-Saharan Africa, Pakistan, with outbreaks reported in European countries such as Italy), tick-borne encephalitis (Western Europe, Russia, China). After a mosquito (Aedes sp. Culex sp) or tick bite (Ixodes), there is virus replication which results in viremia and subsequent dissemination into the CNS.

Neuroinfectious diseases

write a section indicating a wide variety of infectious and the training and research opportunities in the general area. [This applies to neuropharmacology fellowship as well – it is open to negotiation and can vary from basic science related to neuro immunology to clinical infectious disease work. ]

Multiple sclerosis

About MS

Multiple sclerosis affects over two million people worldwide. It is presumed to be autoimmune, although the exact etiology is not fully understood. MS begins as a relapsing remitting disease (RRMS) in >80% of patients and ultimately becomes progressive in >50% of untreated RRMS patients. patients with progressive MS accumulate neurologic disability, with or without discrete relapses. MS is more common in females, with the current female: male ratio in North America and in Europe estimated at 2-4:1.

Recent genome-wide association studies indicate that many genes affect the risk of MS, although most confer only a small risk of diseases. Environmental factors also confer risk for MS, including low vitamin D blood level, high body mass index during adolescence/young adulthood, and smoking cigarettes.

Classically, MS causes demyelinating CNS white matter lesions with relative sparing of axons. Active lesions in white matter are characterized by perivascular mononuclear cell infiltration, with a variable presence of antibody and activated complement. Despite its categorization as a “white matter disease,” gray matter is frequently damaged in MS. Gray matter lesions can occur in deep gray matter structures such as the thalamus as well as in the cerebral cortex. These lesions have been under-recognized because they are difficult to see by MRI, and are often not well appreciated pathologically without special stains. Active white matter lesions display blood-brain barrier (BBB) breakdown, which is manifest on MRI gadolinium enhancement. This BBB breakdown is rarely seen for cerebral cortical gray matter lesions.

MS patients can have a myriad of symptoms and signs. Common presentations include optic neuritis, diplopia, transverse myelitis, brainstem syndromes, and sensory disturbances. Three main clinical subtypes are defined based on clinical course: relapsing remitting, secondary progressive, and primary progressive. Relapsing-remitting MS is characterized by clinical stability between individual attacks from which the patient may or may not fully recover. This is the subtype of MS that responds best to the current disease-modifying therapies (DMTs). Secondary progressive MS patients have gradual neurologic deterioration and may also have superimposed attacks. Secondary progressive MS develops following an initial relapsing-remitting course in a substantial proportion of RRMS patients. About 10% of MS patients have primary progressive MS, which is characterized by gradual downhill progression from onset without any clinical attacks. The underlying pathophysiology of progressive MS is not well understood, but culminates in progressive axonal loss.

MS treatments include the treatment of symptoms, treatment of acute relapses, and DMTs.  Relapses that alter function or cause pain are typically treated with corticosteroids, but corticosteroids do not alter the long-term prognosis. A number of DMTs are now available for patients with relapsing MS, including older injectable medications such as the beta-interferons and glatiramer acetate, and newer oral agents such as fingolimod, dimethyl fumarate, and teriflunomide. Also, there are several DMTs administered by infusion, such as natalizumab. Despite the several available DMTs with differing mechanisms of action, not all relapsing disease can be well-controlled. Better therapies for patients not responding to current DMTs, as well as DMTs that halt progression, are needed.

HIV-associated neurocognitive disorder (HAND)

About HAND

HIV has long been associated with a spectrum of neurologic disorders ranging from mild impairment of function only recognized with detailed, quantitative testing to completely disabling dementia. In spite of the success of modern HIV therapies that greatly expand lifespan and capacity, HIV-associated neurocognitive disorder, or HAND, continues to impair as many as half of all patients with HIV.

With more than 30 million HIV patients worldwide, this prevalent source of neurological disability requires ongoing attention. HIV care from Washington University physicians and specialists is informed by ongoing research to characterize HAND so that it may be more effectively recognized and treated.

CNND faculty including David Clifford, MD, and Beau Ances, MD, regularly teach current best practices for diagnosis and treatment of HAND and other neurological complications of HIV. Multiple ongoing research programs at the School of Medicine help to inform our understanding of these disorders. Lectures and seminars are offered to medical students, residents and fellows in training, as well as at departmental teaching conferences such as Grand Rounds. A post-residency fellowship is available to support advanced learning about HAND as well as to actively participate in the identification and care of patients with this disorder.