Neuro exam 1 part 2 Flashcards
Hematology
Pathophysiology of MS
- MS is a disease which results in neurologic dysfunction due to degradation of myelin
- o Myelin is fatty substance which surrounds the nerve axon allowing signal to be transmitted from one location in the CNS to another distant location with greater speed and efficiency
- • This autoimmune process causes focal areas of demyelination with associated inflammation that slows down or completely interrupts transmission of neural activity
MS is a life-long disease which presents in what two distinct forms
Relapsing Remitting MS (RRMS)
- ▪ This is the most common form of MS and is defined as distinct acute exacerbations of demyelinating disease that result in transient neurologic dysfunction lasting days to weeks, before typically resolving completely, leaving the patient at or very near to their previous neurologic baseline
- ▪ RRMS accounts for >90% of all MS cases
- Patients with longstanding RRMS will often transition into a Secondary Progressive MS (SPMS) disease category many years after initial symptom onset
- • SPMS is defined as incomplete return to baseline in patients following exacerbation with a history of longstanding RRMS.
- • Approximately half of RRMS will become SPMS at some point.
Primary Progressive MS (PPMS)
- ▪ PPMS is the rarer form of MS and is defined as distinct acute exacerbations of demyelinating disease that result in permanent neurologic dysfunction. The patient may show some subtle signs of improvement but they fail to return to their previous neurologic baseline
Epidemiology and Risk factors of MS
MS affects greater than 350,000 patients in the US alone
- o Prevalence of ~10-20/100,000 in the population
• There are clear associations with both genetics and environment
- o Individuals in northern climates develop MS at a strikingly high frequency than those who were raised in southern areas
- ▪ Some postulate a link to Vit. D deficiency but this has never been fully supported in the literature
- Onset of symptoms is typically noted between the ages of 20 and 40, but the disease can occur at nearly any age.
- Females carry a 2-3x risk of developing MS compared to males
- Those with first degree relatives carry a 20-40x risk of developing disease compared to general population
- o There is also a slightly elevated risk of developing MS if other autoimmune diseases are present in first degree relatives
Prototypical presentations of MS
I will begin this section with the preface that MS can present with nearly any imaginable neurologic impairment, ranging from monocular blindness to ataxia to tremor to even quadriplegia. The disease examples below represent the most common initial presentations of demyelinating diseases and are by no means all encompassing. I am specifically seeking to provide the most frequently seen and tested clinical presentations so that you will be familiar with them when they encountered in the clinic or in a question stem.
- Optic Neuritis
- Intranuclear opthalmoplegia (INO)
- Transverse myelitis
Define the clinical features of optic neuritis,
Optic Neuritis
o Very common clinical syndrome resulting from MS
o This is defined as acute demyelination of the optic nerve
- ▪ Typical anterior to the chiasm and only involving one of the optic nerves (left or right), but has been known to involve both nerves and/or the chiasm in rarer presentations
- ▪ Symptoms of a typical optic neuritis are as follows:
- Gradually progressive monocular vision loss often described as hazing or blurring. Many patients will described the sensation of looking through “dirty dishwater” or a “dense screen”
- o Symptoms usually worsen over hours to a day
- o If vision loss is very abrupt (i.e. over seconds to a minute) you should be thinking vascular (stroke of the retina) not demyelinating
- • There is loss of brightness and clarity of color. This is termed color desaturation.
- • Patients will often described a dull ache when looking up, down, left or right.
▪ Exam findings will be remarkable for an afferent pupillary defect and decreased visual acuity in the affected eye. One may also appreciate optic disc edema on funduscopic exam, but this usually takes a couple of days following symptom onset to be readily apparent.
▪ Symptoms usually resolve to previous baseline within weeks, but the afferent pupillary defect may remain a permanent exam finding
Describe features of intranuclear ophthalmoplegia (INO)
o An INO results from a lesion within the brainstem, most specifically within the pons.
o INO is defined as an impairment in horizontal gaze where the affect side has failure of medial gaze (towards the nose) when looking away from the side of the lesion (see below)
- ▪ The INO results from a disconnection of the abducens nucleus to the oculomotor nucleus due to demyelinating disease occurring in the medial longitudinal fasciculus (MLF). The impaired connection results in dis-conjugate gaze with nystagmus in the good eye
Describe clinical features of transverse myelitis
Transverse Myelitis
- o Transverse Myelitis is demyelination of the spinal cord.
- o As you may recall the spinal cord is formed by various tracks, which house fibers with vastly different functions (i.e. corticospinal fibers carry motor input from the brain to the body). Keeping this knowledge of spinal cord anatomy in mind, you will understand why a transverse myelitis can result in a wide ranging of neurologic symptoms ranging from hemi-sided weakness, sensory deficit (of different types), bowel/bladder dysfunction or some combination of all of the above depending on the location and size of the demyelinating plaque.
Diagnosis of MS
- No single test of clinical feature in isolation is significant enough to establish or exclude the diagnosis of MS
- MS often requires extensive history, neuroimaging, and at times additional work-up with cerebrospinal fluid analysis, and prolonged clinical monitoring to establish the diagnosis.
- The diagnosis of MS hinges on the principal of “separation of lesions in time and space”
- o The diagnosis of MS is reliant on a patient having more than one clinical symptom which is consistent with demyelinating disease. These clinical symptoms must be separated in time. It also is necessary that those two or more clinical symptoms localize to different places in the central nervous system
The term “separated in time and space” is the main principal for the McDonald Criteria which is used to clinically make the diagnosis.
o A single episode of demyelinating disease without history of prior transient neurologic deficit is considered a clinically isolated syndrome. This is NOT diagnostic for MS (only a single clinical event, not multiple as is required by the McDonald Criteria), however there is most certainly an increased risk that the patient will develop MS in the next five years compared to the baseline population.
- ▪ Frequent monitoring and follow-up MRI is important in patients who have had a clinically isolated syndrome so that the diagnosis of MS is not delayed.
o Neuroimaging and CSF studies are also helpful in making the diagnosis, but are not a required element in the McDonald Criteria to definitively diagnose MS
• Neuroimaging is mainly focused on the results of magnetic resonance imaging (MRI) rather than CT. In general CT imaging is not helpful in diagnosing MS.
- o MRI’s give very detailed imaging that can reveal current as well as older evidence of demyelination which is extremely useful in supporting the diagnosis of MS
- o Typical features present on MRI include multiple ovoid or confluent white (hyper- intense) areas on the T2 Flair sequence that are often location along the ventricles, corpus callosum, in the brainstem, and cerebellum.
Cerebrospinal Fluid Analysis
o Obtaining CSF and analyzing is for the presence of abnormalities that can be seen in MS can aid in establishing the diagnosis, but are not diagnostic in isolation (meaning it’s just one “piece of the pie” that can support the conclusion that MS is the etiology of the patient’s symptoms
o Abnormalities which can be seen in the CSF of a patient with MS include: oligoclonal banding, abnormally high IgG/albumin ratio, and elevated IgG synthesis rate
o The CSF findings are often absent early in the disease course and present only in approximately 80% of those who suffer with MS
▪ Key point: If the findings of abnormal CSF are present they are helpful, if they are absent it definitely does not exclude the diagnosis of MS.
Treatment options of MS
**Acute exacerbation
Treatment of the acute exacerbation
- o When a patient presents with an acute MS exacerbation, which may clinically appear as an optic neuritis, intranuclear ophthalmoplegia, transverse myelitis or any number of other neurologic deficits, one must keep in mind the basic pathophysiology of the underlying disease. Specifically you must remember that inflammation around the affected part of the nerve is large component of what contributes to the clinical presentation
- o Understanding the role that inflammation plays helps to rationalize why we use high dose corticosteroids to treat MS flare-ups.
- Although we know that patients who have RRMS do get better on their own, often returning to their previous neurologic baseline within weeks to months, we also know that offering treatment with steroids will likely increase the speed of recovery significantly.
- o Typically patients are given 3-5 days of very high dose IV methylprednisolone treatment at the onset of certain significantly symptomatic MS exacerbations such as those clinical presentations listed above. More minor complaints, such as mild sensory impairments, may be treated with lower doses of oral steroids or just monitored clinically for resolution on their own as the risk of side effects from the steroids does not outweigh the benefits of a more rapid recovery
Selected long term treatment of MS
The theory that MS is an inflammatory autoimmune condition guides the mechanisms of action for the available disease modifying therapies.
o These drugs only work in the setting of relapsing remitting MS; there are no available treatments to alter the course of primary progressive MS at this time.
o There are six main disease modifying therapies available to treat MS (three of which are interferon beta agents)
Interferon beta treatments
- ▪ The exact mechanisms for the interferon beta agents are unknown aside for some action on decreasing T-cell migration. All interferon therapies have been shown to decrease the number of clinical exacerbations and to slow the creation of new T2 Flair hyper-intense lesions in the brain. The interferon beta agents are detailed below.
- ▪ Individual drugs (no need to memorize)
- • Interferon beta-1b (Betaseron™)-subcutaneous injection 3x weekly
- • Interferon beta 1a (Rebif™)- subcutaneous injection 3x weekly
- • Interferon beta 1a (Avonex™)-intramuscular injection 1x weekly
- o Less efficacious in aggressive disease compared to the above two choices
- ▪ All the interferon treatments have side effects of flu-like symptoms (headaches, arthralgia, myalgia, and injection site reactions.)
Glatiramer Acetate (Copaxone™)
- ▪ This drug most likely acts in the inflammatory process by interacting at the level of the major histocompatibility complex.
- ▪ Given as a daily subcutaneous injection
- ▪ Fewer side effects than the interferons betas, but this drug is also found to be less effective in aggressive disease compared to the subcutaneously administered interferon beta drugs
o Gilenya (Fingolimod™)
- ▪ It binds to certain sphingosine-1-phosphate receptors which may sequester some lymphocytes in the lymph node and prevent them from entering the brain
- Early trials show it to be as efficacious as the interferon beta treatments
- ▪ Can cause significant bradycardia and hypotension in some patients with the first dose therefore the patient must be monitored in physician’s office or hospital based setting for this reason
o Teriflunomide (Aubagio™)
- ▪ Limits an enzyme in pyrimidine synthesis pathway in lymphocytes which blocks proliferation of activated T and B cells which are responsible for the inflammation in MS
- ▪ Can result in teratogenicity. If patient becomes pregnant it must be removed from system with cholestyramine- Pregnancy category X
- ▪ Common side effects: Diarrhea, nausea, alopecia (resets hair cycle),risk of hepatotoxicity.
o Dimethyl Fumarate (Tecfidera ™)
- ▪ Activates the Nrf2 pathway which is involved in the cellular response to oxidative stress
- ▪ Common side effects: Flushing, diarrhea, nausea, 20% reduction in lymphocyte level
o Natalizumab (Tysabri™)
- ▪ This IV based infusion is only given to patients with very aggressive disease who have failed lower risk therapies
- ▪ Works by binding to the alpha 4-integrin at the blood brain barrier and in-part blocks lymphocytes from entering into the brain
- ▪ Risky medication, which carries a significant risk for the development of progressive multifocal leukoencephalopathy (PML) which invariably causes death.
Identify other selected demyelinating disease (NOt MS)
Neuromyeltis Optica (Devic’s Disease)
- o It is a relapsing inflammatory demyelinating disease that most commonly affects optic nerves and the spinal cord, leading to sudden vision loss or weakness in one or both eyes, and loss of sensation and bladder function.
- o Does not typically cause the same volume of subcortical white matter lesions
- o Can be assessed by ordering serum NMO IgG antibody
- ▪ Antibody to Aquaporin 4 Chloride Channel
- o Treated with Rituxumab (Rituxan™)
- ▪ The antibody binds to CD20 which is widely expressed on B cells, from early pre-B cells to later in differentiation.
- ▪ Rituximab induces CD20 expressing B-cells to enter apoptosis
Differentiate btw NMO vs MS based on
- Distribution of symptoms and signs
- Attack severity
- Head MRI
- COrd MRI
- CSF cells
- Oligoclonal bands
- Permanent disability
- femal patients
- coexisting autoimmunity
- serum neuromyelitis optica antibody
A 36 y/o woman presents for evaluation of worsened gait over the last 8 years. She has been seen by multiple neurologists and diagnosed with relapsing multiple sclerosis due to history of gait impairment, spasticity, weakness, neurogenic bladder and sensory decrement in the appendages. She has been tried on four different disease modifying therapies all of which appear to have failed given continued accumulation of symptoms and MRI lesions
Primary Progressive MS
- PPMS is a variant of MS that fails to respond to disease modifying therapy
- Patients with this form of the disease account for <10% of all MS cases.
- Generally this is a diagnosis made in retrospect after trying and failing multiple agents
A 32 y/o female with history of RRMS presents to the ED because she awoke with symptoms of right lower extremity numbness and weakness which have been gradually worsening throughout the day. Prior to going to bed she stated she felt fine. She denies pain. She feels as though she is able to void normally. She has been managed on Interferon Beta 1-a (Axonex) for the last 7 years. During the last 2 years she has had three relapses, the last two she has failed to recover completely from her new symptoms. Her last MRI was two years ago.
Physical Exam:
- General Exam: Normal
- Neurologic Exam:
–Mental Status: Normal
–Cranial Nerves: Normal
–Strength: 4/5 weakness in all muscle groups of the right leg.
–Sensory: Decreased sensation to pinprick, temperature, and light touch in the leg
–Coordination: Normal
–Reflexes: 3+ throughout. Right toe is upgoing
–Gait: hemicircumduction of the right leg
Transverse Myelitis
- Transverse Myelitis is demyelination of the spinal cord.
- Transverse myelitis can result in a wide ranging of neurologic symptoms ranging from hemi-sided weakness, sensory deficit (of different types), bowel/bladder dysfunction or some combination of all of the above depending on the location and size of the demyelinating plaque.
A 30 y/o man presents with complaints of 3 days of blurred vision in the left eye only. He has eye pain with extraocular movement. No other neurologic complaints. No past history of neurologic symptomatology. No family history of autoimmune disease.
Physical Exam:
- General Exam: Normal
- Neurologic Exam:
–Mental Status: Normal
–Cranial Nerves: Afferent pupillary defect on the right. Decreased visual acuity with 20/200 vision on the right, normal on the left. Normal eye movements though he does have pain
–Strength: Normal
–Sensory: Normal
–Coordination: Normal
–Reflexes: Normal. Toes are downgoing
–Gait: Normal
Optic Neuritis
- •Optic Neuritis is one of the most common presentations of demyelinating disease
- •Typically presents with complaints of progressive vision loss over days
- –Some liken it to looking through dirty dishwater or a dense screen
- •Typically has mild pain with extraocular movements
- •Usually optic disc swelling can be seen after the first few days of clinical symptoms (sometimes earlier)
A 30 y/o man presents with complaints of 3 days of blurred vision in the left eye only. He has eye pain with extraocular movement. No other neurologic complaints. No past history of neurologic symptomatology. No family history of autoimmune disease.
Physical Exam:
- General Exam: Normal
- Neurologic Exam:
–Mental Status: Normal
–Cranial Nerves: Afferent pupillary defect on the right. Decreased visual acuity with 20/200 vision on the right, normal on the left. Normal eye movements though he does have pain
–Strength: Normal
–Sensory: Normal
–Coordination: Normal
–Reflexes: Normal. Toes are downgoing
–Gait: Normal
MS
–Despite this being the first attack, the revised McDonald Criteria suggests that this patient does now suffer from MS and disease modifying therapy should be initiated.
–If you are not certain then additional work-up can always be obtained.
- A 27-year-old man comes to the office for advice about treatment of his recently diagnosed multiple sclerosis. Three years ago, he had an episode of diplopia that resolved entirely after 2 months. One month ago, he had a mild weakness and numbness of the right leg. MRI of the brain at that time showed multiple cerebral white-matter lesions in a periventricular distribution classic for multiple sclerosis. His leg weakness resolved without treatment. He is now asymptomatic and has a normal neurologic examination. Which of the following is the most appropriate treatment recommendation at this time?
A. High-dose intravenous methylprednisolone
B. Chronic oral prednisone
C. Interferon-beta
D. Observation - A 29-year-old woman comes to the office because of gradual loss of vision in her left eye over 5 days. The problem started as a “smudge” in her central visual field and gradually worsened such that she cannot read with her left eye. She has pain with left eye movements and has difficulty working because of the impairment. Neurologic examination is unremarkable except for her eye findings. Visual acuity is 20/20 in the right eye and 20/400 in the left eye. Visual field testing shows a dense central scotoma on the left. Funduscopic examination is normal. There is a left afferent pupillary defect. MRI of the brain is normal. Which of the following is the best initial course of treatment for this patient?
A. Intravenous methylprednisolone
B. Interferon-beta
C. Glatiramer acetate
D. Aspirin
E. Natalizumab
- C
- A
Overview of Rhabdovirus
Rabies virus, a member of the family Rhabdoviridae, causes a disease of the central nervous system, which often has a protracted incubation period. The prognosis, once disease is apparent, is almost invariably fatal. Rabies in man is usually contracted following the bite by an infected animal or inhalation of aerosol droplets from rabies-infected bats. Further, rabies does not appear to be the result of an encephalitogenic variant of wild-type virus, nor does it result from immunologic defects of the host. On the contrary, rabies has been shown to multiply actively in both neural and extraneural tissues. Further, effective vaccine exists for humans and animals, which may account for the low incidence of clinical rabies in domestic animals and in man.
The purpose of the lecture is to briefly discuss the replication processes of Rhabdoviridae. This replication scheme will serve as the prototype for single stranded, non- segmented,(-) polarity RNA containing viruses. Also, the pathogenesis and control of rabies will be considered. (Remember Influenza virus replication was the model for single-stranded, segmented negative polarity RNA).
- What polarity is the viral genome and how are the progeny RNA formed?
- SS RNA, (-) polarity, nonsegmented
- RNA dependent - RNA polymerase = L + NS protein, other enzymatic activities are associated with this complex
- helical nucleocapsid, RNA + L, NS, N
- bullet-shaped capsid contains 5 structural proteins; L, NS, M, G, N, rhabdoviruses are the only ones with bullet shaped virions
L = large NS = nucleocapsid small
M = matrix G = envelope glycoprotein N = major nucleocapsid
- Posses an envelop; glycoprotein (G) produces neutralizing Ab, acts as hemagglutinin, and inhibits cell processes (may have toxic properties on its own
- Describe replication of rhabdovirus
- Replication and transcription
Replication scheme: Virus particle attaches to receptors on the surface of cells. Receptors vary with cell type; 1) nicotinic acetylcholine receptor (AChR) and 2) neural cell adhesion molecule ( NCAM). The virus enters into the cell by phagocytic engulfment into endosomes and then fusion between the viral envelop and the endosomal membranes, thereby releasing RNA into the cytoplasm of the cell.
Replication of Rhabdoviruses (See Influenza as a prototype replication scheme:
Genome Replication And Transcription:Occur in the cytoplasm:
- Two events must occur relative to the viral genomic RNA.
1. Transcription: The negative (-) polarity genomic RNA must be converted to + polarity mRNA which is translated into viral proteins
Transcription: - viral RNA —> ++++ mRNAs (5 mRNAs formed) Each of the 5 viral mRNAs translated into one of the viral proteins
-
Genome Replication: Many new copies of progeny, negative-polarity genomic RNA must be synthesized. — ++++
- viral RNA —> +++ RNA (RI) —-> — RNA (RI)
Recall: RI is the Replicative intermediate
Viral progeny buds from a site of the plasma membrane to form a bullet shaped virus, which has G glycoprotein extending from it’s envelop on its outer surface
Identify 3 phases of Rabies
1. Incubation phase- prolonged weeks to months
2. Prodromal phase – fever, malaise, headache, sore throat, vomiting, nausea; Viral transport called “Retrograde Axoplasmic)
Rabies virus infects peripheral nerves, replicates in dorsal ganglia and travels up spinal cord to brain
3. Neurological phase- Infection of the brain Rabiesvirus descends to infect eye, glands and visceral organs
- excitement stage - apprehension, fright, hydrophobia (fear of water) (biting stage in dog) - fear of space (air) aerophobia
- manic stage - convulsions, usually death
Other modes of transmission of rabies
Alternative Mode of Transmission: Bats become infected, replication of virus occurs, but no disease results. Virus in saliva and aerosols of saliva are also mode of spread. Most rabies virus infected patients cannot document being bitten by bat.
Animal Bites: Skunks, foxes and raccoons are also primary hosts for rabies virus in US. Dogs are minor sources in US, but are # 1 source in most of the world. Cattle are also infected with rabies in many parts of the world.
Puppy Pregnant Syndrome (Please look it up)
Virus enters host through bite or scratch of rabid animal. The virus is found in animal’s saliva, CNS, urine, lymph, milk, blood. A hunter, who is skinning and dressing an infected animal and accidentally cuts him or herself during the process can acquire the infection.
Rabies initiated by corneal transplants
Details about rabies virus infection
The virus usually remains localized after bite for extended time period. The incubation period is from 10 days to 2 years- usually 2-3 months. This corresponds to the time to multiply in muscle or connective tissue at the bite site and begins to move along the peripheral nerves. The prodromal stage begins (see above) and the virus transcends to the CNS.
Once the CNS is reached, virus multiplies in CNS. Next the virus descends along the peripheral nerves to salivary glands and other organs/tissues. For a rabid dog the virus in the saliva allows it to bite and infect another animal or human. The CNS infection leads to destruction of cortex, midbrain, pons, medulla, posterior horn of SC. What virus infects the anterior horn specifically?
Rabies rarely causes inflammatory lesions
Neutralizing antibody arise late in the course of infection, however, it is too late to prevent the disease course
Diagnosis of Rabies
- Negri bodies in CNS (brain) of animal, cytoplasmic inclusion, seen in cells from brainstem of infected humans
- Detection of virus (viral antigens or viral RNA) from saliva, serum or “corneal impressions”, skin and brain biopsies
RT-PCR used for detecting viral RNA, rapid and a preferred method; saliva is conducive to rapid testing
RT = reverse transcriptase
Direct immunofluorescence test (gold standard) of animal tissue, brain of animal is submitted to state health department or region lab for evaluation
Rabies variants are associated with bat species, canine variants also recognized
Rabies specific antibody appears late and its detection is not allow diagnosis
Development of Rabies vaccine
Vaccine Historical Development
Long incubation period provides a window of time to immunize and produce high titer circulating antibodies
Semple - rabiesvirus infected nervous tissue, which is inactivated with phenol
- requires 7-14 daily injections
- evokes allergic encephalomyelitis complications
Human diploid cell vaccine - 4 doses, 0, 3, 7 , and 14 days
- expensive
- prophylactic —animal handlers, 3 doses
- ab levels elevated > 2 yr
IM route of administration of HDCV depending
IM- Adults given deltoid ( IMOVAX RABIES)
- Children given in anterolateral aspect of thigh or deltoid
- Gluteal muscle not appropriate (too much fat in butt)
~20,000 people received rabies post exposure prophylaxis/year
~18,000 people received preexposure prophylaxis/ yr
Rabies vaccine, adsorbed (RVA) Licensed 1988,inactivated virus adsorbed to aluminum phosphate
Less expensive Chick Embryo grown vaccine and Vero Cell grown vaccine are now available.
Recombinant vaccinia vaccine, Controversial vaccine expresses rabies G envelope protein, proposed vaccination of raccoons and other wildlife
Treatment of human bitten by rabid animal or expected rabid animal
- First action
- On day 0
- Start vaccine when?
First action: Flush wound with soap and water and cleans thoroughly
On day 0 inject 1/2 of Human rabies immune globulin ( (HRIG) directly into the wound and inject 1/2 of HRIG IM,
Start vaccine on day 0, don’t administer HRIG and vaccine at the same site; Remember 4 doses: 0, 3,7,14
HRIG- HYPERAB and (IMOGAM)
1/2 life of ab after administration = 21 days
Filoviridae vs rhabdoviridae
Filoviridae family - Enough differences from Rhabdoviruses to be classified as a separate family, differences in protein size, enveloped, neg. stranded RNA: In structure it resembles a piece of spaghetti and is not bullet shaped like Rhabdovirues
Marburg virus, African hemorrhagic fever (liver is involved, encephalitis)
Describe 2 Hemorrhagic fever viruses
Ebola - antigenically distinct from Marburg, morphologically similar
- a. Marburg - found in monkeys and derived tissue culture cells - infects laboratory workers
- b. Marburg and Ebola - high fever, headache, myalgia, diarrhea –> conjunctivitis, rash, abdominal pain —> hemorrhage skin, nose, GI, GU —> shock, death 53-88% mortality
- c. Natural route to transmission is through person to person contact via infectious biological fluids; Ebola (2014 caused signicant numbers of fatal disease in West Africal
Ebola virus is a potential agent for Bioterrorism. The Japanese cult, Aum Shinrikyo, who released Sarin nerve gas into the Tokyo subways several years ago, sent cult members to Africa during the outbreak of Ebola to obtain biological samples.
Since Ebola virus is difficult to grow in tissue culture, it is most likely problematic to grow enough virus to produce WMD. It still provides a subject of movies, however.
Ebola outbreak in West Africa (2014). 370 Deaths as of July 1, 2014. Spread by human-human transmission perpetrated by poor public health systems.
The Russians researched many of the “hemorrhagic fever viruses” and attempted to weaponize them as part of Biopreparat. As discussed in the video “Plague Wars”, the lethal nature of Marburg virus was demonstrated by the accidental inoculation of a Russian scientist with the agent. The scientists isolated the virus liver and spleen of the decease individual in hopes of developing a more virulent form of the virus.
Remember some other hemorrhagic fever viruses are Arenaviruses, Bunyaviruses and Flaviviruses.
Overview of Zoonotic diseases
Zoonotic diseases are caused by numerous microorganisms including viruses. The animal is the primary host and humans are considered to serve as accidental or peripheral hosts. The zoonotic virus can be transmitted to humans via insect vectors or by excretions of the infected animal that contaminate the human environment. The outcomes of possible virus infections are varied and these infections can be targeted to one organ system or be multi-system in scope.
Viruses that are transmitted by insect vectors fall under the general category, arthropod borne viruses or arboviruses. Insect vector mediated transmissionof viral diseases is multi- factorial and depends on ananimal hostserving as a reservoir for viral infection. Another important factor is the presence of aninsect vector(mosquitoes, ticks, sandflies, etc) capable of biting the infected animal and transmitting the virus to other animals or to humans as an accidental host. The insect serves as aninstrument of transmission, whereby thevirus actually replicates in the insect to produce increased numbers of infectious virus particles. Greater numbers of infectious particles increase the likelihood of transmission to humans.
What is a key factor in arbovirus transmission
A key factor in arbovirus transmission is the availability of arthropods in a given geographical area. Colorado tick fever is found in western United States because the tick is resident in this environment and the species of tick is an essential part of the transmission process. Nicolas County, West Virginia is a “hot-spot” for LaCrosse encephalitis because the mosquitoes live in the hardwood trees in that environment and are capable of being infected and transmitting the virus to individuals living in or entering into that geographical region. As man ventures into environments once spared from human intervention, such as tropical jungles, in order to harvest trees or clear cut jungles for agricultural use, humans are being exposed to new constellations of viruses. Likewise certain environmental factors have allowed insect vectors to survive outside their original niche. Global warming, for example, allows temperature sensitive insect larvae to now survive winter months in northern climates. It often takes a span of weeks to months of freezing temperatures to kill insect larva located deep in the soil. It has already been noted by the CDC that the mosquito responsible for transmitting dengue viruses (flaviviruses) has been isolated from as far north as Kentucky. This will more than likely be a common theme rather than an exception.
Describe the “jungle” (rural) cycle
In classical epidemiological terms the “jungle” (rural) cycle refers to a process whereby insects naturally resident in the jungle transmit a viral infection to animals that also live in the same environment, Aedes hemagogus being an example. In a similar manner certain insects, Aedes aegypti mosquito, for example, are well adapted to living in an urban environment and are capable of transmitting arboviruses between animal hosts. It is possible that the rural and urban cycles can intersect if animal/human hosts move from one environment to another or, alternatively, the insects span the two environments.
Differentiate the the families in arbovirus
Arboviruses are a rather diverse group of viruses and members of several viral families are transmitted by insect vectors. These include:
In excess of 300 different viral agents generally designated as arboviruses are members of the Togaviridae, Flaviviridae , Bunyaviridae, and Reoviridae . These viruses are transmitted to man by arthropod vectors, usually mosquitoes. Arboviruses multiply in both the vertebrate host and the insect vector, often causing disease in the vertebrate host, but no disease in the arthropod. The incidence of arthropod-borne infections is high, especially in tropical areas and in temperate climates. Clinical disease in man ranges from an undifferentiated febrile illness to an encephalitis and multi-organ system disease.
- What is the role of mosquitoes in maintenance of arbovirus infections?
There are more than 300 known arboviruses. Most are recovered from mosquitoes or ticks.
Arboviruses; group of viruses containing several families of Arthropod Born and related viruses
Approximately 100 infect man. About 40, mostly togaviruses and flaviviruses, produce significant disease, which may include the following:
- Encephalitis
- Hemorrhagic fever; tick-borne Russian spring-summer, yellow fever, dengue with shock syndrome
- Fever + Rash; Dengue fever alone without complications associated with the hemorrhagic form
Many arboviruses are endemic to tropic but they can also cause sporadic epidemics in temperate zones.
First Arbovirus discovered - Yellow Fever Virus. The first disease in which it was established that a virus was an agent of human disease and that insects could serve as a vector.
Togaviridae structure
Classified into Alphavirus and Rubivirus (rubella). Rubella virus is NOT an arbovirus, whereas alphaviruses are arboviruses
The structure of Alphaviruses include an icosahedral capsid surrounded by an envelope, which covered with fine glycoprotein spikes. To differentiate it from Flaviviruses (see next section) Togaviruses are protease sensitive particles.
Togaviruses have a SSRNA (+) polarity genome which code for 4-5 viral proteins. Viral multiplication occurs within cytoplasm and acquire their envelop by budding at cell membranes.
Replication scheme that was presented for poliovirus will suffice for all of the + stranded RNA viruses
Clinical manifestations of togavirus
First stage of Togavirus (alphavirus) infection: Togavirus infections are all similar in initial stages.
Virus is introduced into blood via the insect bite, removed from circulating blood and multiples in RE system (esp. spleen and lymph nodes). Viremia then follows (systemic phase of disease) and is associated with minor illness, chills, fever, vomiting, pain. (1st stage symptoms)
Second stage of Togavirus (alphavirus) infection which leads to an encephalitis.
Virus crosses Blood Brain Barrier which causes lesions in all parts of brain. This is accompanied by neuronophagia (phagocytic destruction of nerve cells) and encephalomalacia (destruction of neurons + support structures). Symptoms include neck muscle rigidity, confusion, and convulsions (CNS symptoms).
Give examples of alphaviruses that cause encephalitis
Eastern Equine Encephalitis (EEE) causes severe human illness often with a high mortality (50-70%). It is the least prevalent of the various equine encephalitis viruses in the US. It has a higher incidence in certain geographical areas due to heavy spring rains and higher numbers of mosquitoes in a geographical region.
Experimental vaccine is available to lab workers, but horse vaccine available commercially. Reduction of EEE in horses, which is its natural host, leads to less of a chance of humans being bitten by infected mosquitoes and transfer of the virus to humans who serve as an accidental host.
Western EE - less severe - 2-3% mortality
Venezuelan EE - primarily in horses - mild in man - 0.5% mortality
Name given to these viruses does not necessarily indicate actual geographic distribution of the virus. The name reflects the location where it was first isolated and there may have just as high an incidence in other locales.
Identify Host-Alphavirus interaction
In WEE (western equine), who is more susceptible to infection (children vs adults)? ****
Chikungunya Virus has symptoms very similar to Dengue Fever Virus (Flavivirus, see below).
Symptoms include acute fever, joint pain, maculopapular rash on trunk and possibly limbs, headache, nausea, vomiting, conjunctivitis and retinal lesions
Chikungunya is an Arbovirus transmitted by mosquitoes.
Chikungunya must be distinguished from Dengue in order to determine treatment with NSAIDs and fluids. Aspirin is not recommended for Dengue because aspirin can enhance hemorrhaging .
Age factors relative to clinical disease:
WEE infects children at a rate of 50:1( infections/clinical case). In adults the WEE rate of infection is 1000:1 infections./clinical case) and most are asymptomatic. In the case of EEE infections most fatal infections are seen in the elderly, ie >30 % fatality rate.
Flaviviridae family
- trasmited by what insects?
- Clinical manifestations
Family: Flaviviridae
Have many structural and replication features that are similar to Togaviruses
Flaviviruses are protease resistant and 20-50 nm in diameter
Transmitted by mosquito and ticks depending on the virus under discussion
Key members of the Flaviviridae include a number of encephalitis viruses, hemorrhagic fever viruses and rash/fever viruses.
Clinical Manifestations
First Stage of infection by Flaviviruses:
Infected insect bites animal or human and inject virus into blood stream. Replication in RE system and a viremia is established. Fever, chills, malaise, vomiting are possible
Second Stage
Virus invades various tissues during the second stage of infection which follows first stage viremia.
For Flaviviruses that cause encephalitis (St. Louis encephalitis, Japanese encephalitis, West Nile encephalitis and many others) virus crosses the BBB and infects the CNS
Other Flaviviruses cause infections that involve multiple systems. These viruses infect the skin and endothelial cells of the blood vessels as well as various visceral organs. The two primary viruses of this type are Yellow Fever Virus and Dengue virus, the latter having 4 serotypes.
In the category of hemorrhagic fever causing viruses, yellow fever virus or dengue fever viruses cause clinical disease that can be severe. Other hemorrhagic fever viruses are part of other virus families (see Bunya, Arena and Filoviruses)
In certain situations Dengue virus can produce a less severe disease without hemorrhagic fever. In the latter case after the Dengue induced viremia, the virus infects cells of the skin, muscle and viscera.
differentiate 2 examples of hemorrhagic fever virus
Yellow fever vs Dengue fever virus
YELLOW FEVER VIRUS:
Yellow fever is mosquito transmitted. Clinical disease (second stage) includes a very severe, saddle back (diphasic) fever. Infection of the liver causes necrosis of liver (jaundice) and kidney. Hemorrhages occur in stomach which causes the hemoglobin of the RBCs to react with the acid of the stomach to cause a black colored product. Black vomit is characteristic of yellow fever.
DENGUE FEVER VIRUS
Dengue (breakbone) fever is caused by primary infection by one of four serotypes of Dengue virus. The immunity against one serotype does not protect against the other three serotypes. Dengue is endemic in the tropics but can be imported into the US.
Dengue fever in its less severe form appears as a maculopapular rash, pain in joints and muscles. Other symptoms include ocular pain in association with a saddle back fever. Under certain scenarios the initial disease can progress to hemorrhagic fever (DHF) and even further into a shock syndrome.
Progression into a shock syndrome occurs most often, if a primary infection by serotype X (1,3,4) is followed later by a second infection by Dengue virus type 2. An antibody-antigen reaction activates monocytes with the production of cytokines which in turn causes an immunopathology . Concomitant hemoconcentration ( more frequent in females) and thrombocytopenia occur as determined by hematocrit and platelet counts. Acetaminophen is preferred over aspirin, the latter having anticoagulant properties.
Hemoconcentration should be treated aggressively by hydration therapy
Increased frequencies and increased severity of dengue has been reported in the Americas and Caribbean. Significant outbreak in Hawaii have also been reported.
Flavivirus induced encephalitis
- Specific virus
Flavivirus induced encephalitis; West Nile Virus is just one example
West Nile virus ( WNV) first identified in the US in New York about 14 years ago, but now it has spread to almost every state. WNV can be transmitted to humans via 1) insect vector,2)bloodtransfusions,and 3)organtransplants. A viremia is established and the virus crosses BBB to infect the CNS.
Birds and horses seem to be primary animal reservoirs, but dog and cats and a variety other animals have been shown to be infected.
Laboratory Diagnosis of WNV Viral isolation is not practical
Serology test acute and convalescent sera using CF antibodies.
Identify specific virus
- Type of Flavivirus that is transmitted by Aedes albopictus and aegypti, sexual intercourse and blood transfusions
- This specific virus is linked to what 2 conditions?
ZIKA VIRUS
The virus infection has be linked to encephalitis and Guillain Barre syndrome (rarely).
Zika virus has been in the news over the last several years for its ability to cause congenital infections of the fetus, which can manifest a variety of symptoms in the affected individual (developing child) throughout life. Although the virus was first recognized in the late 1940s, it has not been a major concern of health officials until recently. Zika virus infections of humans appears to particularly prevalent in South America and particularly in Brazil. The 2016 summer Olympic Games was held in Rio de Janeiro and athletes, spectators and support agencies traveled to this destination from throughout the world. Without the implementation of appropriate health measures, these groups were susceptible to infection.
Zika virus is an arbovirus that is spread by mosquito vectors, primarily the Aedes aegypti and Aedes albopictus. The virus is a member of the Flaviviridae along with dengue fever and yellow fever viruses, several encephalitis viruses and West Nile virus. A key component in controlling any arbovirus infection is to reduce numbers or eliminate the insect vectors that transmit the virus. Brazil and many other countries do not routinely have processes in place to control insects. Lack of screens on windows, failure to use of insect repellants, failure to eliminate standing water as breeding grounds and lack of air conditioning (windows opened) all contribute to the high prevalence of mosquito vectors. Mosquitoes can lay their eggs in dry season which remain dormant for about 4 months. Eggs exposed to rain can than develop into larvae.
Zika Virus
- Transmission
- antibody
- Vaccine
- Prevention
Zika virus can also be spread by sexual intercourse and blood transfusions in addition to the mosquito bites.
Symptoms include fever, rash, joint pain and inflamed eyes. Muscle pain and headache also reported. Symptoms may last for one week. Most people will have mild symptoms or be asymptomatic.
Serological test and RT-PCR tests available
- RT-PCR of serum collected in the first two weeks of onset of symptoms
- RT-PCR of urine collected within 14 days from onset of symptoms
- Trioplex RT-PCR for Zika, Dengue and Chikungunya viruses
Serum IgM specific to Zika virus is detectable at about one week after onset of symptoms. Clinician should order serology is RT- PCR is negative
Serology (IgM) is also recommended for Dengue and Chikungunya viruses
- 80% + Have a limited disease
- Infection of pregnant women can lead to birth defects, microcephaly
- Guillain Barre Syndrome link being investigate
Vaccine in development, anticipated to be on market in 1.5 years
Prevention: Do not travel to areas where Zika is prevalent
Insect spray, barrier protection, fumigate modes of transportation (airplanes, ships, etc) to eliminate eggs
Eliminate breading areas (standing water)
Type of flavivirus
Condition it causes
flavivirus transmitted by six known species of ticks , four species from genus Ixodes and two from Dernacentor genus. Found primarily in Northeast and upper Midwest. Life cycle includes small to medium size woodland mammals. Man once infected is a terminal host, ie. Tick that bites infected human does not spread virus infection to others.
Powassan Virus
Encephalitis resulting from infected tick bite is rare but if it does occur is often severe with neurological sequelae. Ten % of the severe infections are fatal. Only specialize diagnostic labs have capability to employ serological testing for this infection.
Prevention and control of; Yellow fever, Dengue fever and Encephalitis
Eradication of vector population, eg. Aedes, employing bug spray is a primary method of reducing vector populations. Elimination of insect breeding sites (old tires) and other stagnant water. West Nile encephalitis incidence in New York lead to massive insect spraying (DEET).
In the case of yellow fever, immunization of the human host has been effective. Yellow fever vaccines, 17DD or 17D 204, are composed of live, attenuated virus. Attenuation of virus is produced by passaging YFV in tissue culture cells. Immunization rarely produces complications. Some indication that YFV may provide protection against WNV infections.
The availability of other vaccines for human use is limited. There are no human vaccines for most encephalitis virus infections, however, a vaccine is available for Japanese encephalitis. No vaccine is currently available in US for Dengue fever virus. NOTE: Degvaxia (CYD-TDV) has be developed in Mexico as a 3 dose series (0,6,12 month schedule). Degvaxia has not been “prequalified “ by WHO. Takeda vaccine (TAK-003) shows promise and has better immune response against all 4 Dengue serotypes than the Degvaxia vaccine
Horse vaccines are available to immunize horses which has the potential to interrupt the transmission cycle.
Epidemiology and Bioterrorism concerns of; Yellow fever, Dengue fever and Encephalitis
Epidemiology:
Vector restricted to ecological niche ( fly range), which restricts virus dispersion. SLE virus most common in U.S.
Imported Yellow Fever is possible as a result of global travel. If traveler who is re-entering the US is suspected of having or having been exposed to Yellow Fever, he/she should be quarantined and not allowed to come in contact with mosquitoes.
ArboNet (Arbovirus network):
Human and animal surveillance system to determine the risks of human arbovirus infections. System now monitors continental US.
Bioterrorism Concerns
Many of the encephalitis viruses have been viewed as potential bioweapons. Eastern Equine Encephalitis in particular may be on the “short list “ of arboviruses that could be weaponized. These viruses could be introduced into the animal population, eg. wild birds in the case of WNV, which would serve as a constant reservoir from which human and animal infections could originate. Mosquitoes would serve as the vector for dissemination. Surveillance of the mosquito, animal and human populations are therefore essential. Immunization of horses and spraying for mosquitoes would control the spread of infection.
Arthropod Borne Viruses part 2
In addition to the Arboviruses discussed in the previous section there are viruses within the Bunyaviridae which are also transmitted by insects to cause an encephalitis. Other viruses within this family cause multisystem infections.
**Bunyaviridae - structural characteristics
Structural Characteristics (Bunyaviridae)
Viral dimensions are approximately 90-100 nm diameter. The viral particles have a helical nucleocapsid, which is surrounded by an envelop with glycoprotein spikes extending outward from it surface. (any animal with helical nuceocapsid will have an envelop)
The genome consists of single stranded RNA which present in 3 segments (Large, Medium and Small). Like members of the Orthomyxoviridae (model for negative polarity RNA virus replication), Bunyaviruses have a negative polarity genome and therefore carries a viral RNA polymerase within the virus particle itself. Also like the Orthomyxovirus, influenza A virus, members of the Bunyavirus family can undergo reassortment of RNA segments as a result of mixed infections of cells by different strains of a particular Bunyavirus.
The replication of the Bunyavirus occurs in the cytoplasm and progeny virus particles acquire their envelops by budding through the membranes of the Golgi apparatus.
Bunyvirus are transmitted by ticks and mosquitoes
- How many serogroups? what group cause encephalitis
Genus Bunyavirus
As in the case of the other Arboviruses, a subset of Bunyaviruses can multiply in arthropod vectors and can cause human disease upon being bitten by the infected mosquito.
Some Bunyaviruses are transmitted by mosquitoes and others by ticks.
There are 10 serogroups within the Bunyaviridae and one of these causes encephalitis in humans
California serogroup:
California encephalitis virus is found mainly in the upper Mississippi and Ohio River valleys, where the mosquito vector is most prevalent. The peak incidence of the disease is July through September.
Clinical disease:
The onset of the disease may take mild course or abrupt onset, which includes bifrontal headache, fever, vomiting, sometimes aseptic meningitis. Systemic and meningeal signs abate gradually within a week. 15% of infected children have sequelae.
LaCrosse encephalitis, a member of the California serogroup, is seen in Nicolas County, WV
There are a number of viruses within the Bunyaviridae that are also capable of causing hemorrhagic fevers.
There are a number of viruses within the Bunyaviridae that are also capable of causing hemorrhagic fevers.
Identify genus
Certain members of this genus cause only a febrile illness in humans, whereas others cause Crimean-Congo hemorrhagic fever.
Virus is transmitted by ticks, but the blood and secretions of animals and humans are also infectious.
Genus: Orthobunyavirus
Bunyamwera’ serogroup
Identify genus of bunyaviridae
Clinical symptoms include headache, fever, myalgia, photophobia, stiffness of neck and back and papules over the body surface
Total recovery ensues with immunity for about 2 years
Rift valley fever virus is transmitted by and can infect sheep and other domestic animals which can then be transmitted humans.
Clinical Symptoms: Saddleback fever, acute onset, GI distress, pain in joints and occasionally hemorrhagic fever
Recovery is usually complete. A vaccine has been developed
Genus: Phlebovirus
Phlebotomus fever group are transmitted by sand flies
Identify genus of bunyaviridae
***Pulmonary Condition
Genus Hantavirus:
Korean hemorrhagic fever virus
Hantavirus pulmonary syndrome
Hantavirus infections have also been seen in the American southwest particularly among native Americans. Exposure to virus results from aerosols that originate from mouse feces contaminated dust. The infection often leads to a pulmonary syndrome (HPS)
Higher incidence of HPS is associated with more rainfall in southwest, which provides better habitat quality and increased numbers of rodents.
5% of HPS cases have been confirmed east of the Mississippi River. In July 2004 two cases of Hantavirus Pulmonary Syndrome reported in Randolph County, WV
Ribavirin has shown efficacy in treating HPS if given early in the course of the infection.
Terrorists could aerosolize this agent and disseminate it to produce HPS.
Arenaviridae
- Structural characteristics
Structural characteristics of this virus include a rather wide range of sizes from 50-300 nm in diameter
Virus particles have a helical nucleocapsid which is surrounded by an envelop having a dense lipid bilayer. Within the core particles are seen by EM that resemble ribosomes.
The negative polarity genome of the virus is RNA consists of multiple segments that appear to be circular
Arenaviruses replicate in cytoplasm using a viral RNA polymerase that is housed within the virus particles.
Identify 2 serogroups of Arenavirus
Arenaviruses are divided into two serogroups: 1) The Old World Complex and 2) the New World Complex.
The primary old world viruses are Lymphocytic Choriomeningitis Virus (LCM) and Lassa virus
New world viruses include the Tacaribe virus complex including Junin and Machupo viruses
Virus hosts are restricted to rodents in which persistent infections leads to viremia and/or viruria
Describe old world arenavirus
- associated with rodents
- Clinical disease
- mild with influenza symptoms
- infrequently aseptic meningitis
- organ transplat receipent
- pregnant women exposed to virus can tranmit to fetus and cause death in utero
Lymphocytic choriomeningitis virus (LCM) (Old World Arenavirus)
LCM infects man at frequency of 5%, except for those in close contact with rodents such as laboratory workers.
LCM outbreaks have been reported in humans who purchased hamsters sold as pets. Urine and feces spread the virus. Also found in USA as a result of house mice infections which can transmit the virus to humans and rodent pets
The clinical disease is usually mild with influenza like
symptoms or infrequently aseptic meningitis.
Fatal disease was reported in organ transplant recipients who received organs from an LCMV infected donor. Three of 4 organs recipients died.
Infection of pregnant women during first and second trimester can be vertically transmitted to fetus causing severe disease of fetus.
Severe disease could result from immune complex formation based on studies with a mouse model
Describe old world Arenavirus
- Serious febrile illness
- hemorrhagic fever; cause skin hemorrhages, mouth ulcer and severe muscle acne
- Spread by human to human and rodent to human transmission
LFV causes severe febrile illness in humans with 20% mortality rate. Infection involves many organs, but rarely a benign febrile illness has been documented.
Clinical Symptoms: Seen mostly in Africa, patients develop skin hemorrhages, high fever (hemorrhagic fever) mouth ulcers and severe muscle ache.
Virus spreads from human to human and rodent to human. Rats in Africa are chronically infected throughout their lives and shed high levels of virus in the urine
Describe New world Arenaviruses
- clinical symptos
Tacaribe complex (New World Arenavirues)
These are a group of viruses causing hemorrhagic fever in South America, Trinidad, Florida Everglades, Argentina (Junin)and Bolivia (Machupo). Hemorrhagic fevers often result. Mosquitoes and mites may transmit virus, but rodent urine and feces are the primary means of transmission of animals
Clinical Symptoms: Hemorrhagic fever is characterized by petechiae, bleeding in the GI tract, uterus, nasal cavity and GU tract
15 New world arenaviruses are recognized
Many of the hemorrhagic fever viruses are candidates for weaponization into bioweapons. One possible mode of dissemination of arbovirus caused hemorrhagic fevers is to raise large populations of infected mosquitoes and release them into a human population. The vectors would do the work of the terrorist in transmitting viral agents. This same principle pertains to Toga and Flavivirures that are also transmitted by mosquitoes or other insect vectors.
Understand the definition of cerebral palsy and know its clinical manifestations
Know the various neural tube defects including their pathogenesis and clinical manifestations
- e.g or rostral defects
- caudal defects
- regulators of closure
➤Rostral defects: anencephaly, encephalocele
➤Caudal defects: spina bifida and related conditions
➤Regulators of closure : retinoic acid (teratogen known to lead to neural tube defects in animal models) and folate (inadequate levels significantly increase risk for neural tube defects)
➤Gray matter lined cleft that extends from lateral ventricle to inner table of skull
➤theories : destructive event that disorders later cortical development, segmentation failure, migrational failure
➤Closed lip if surfaces touch each other, open lipped if CSF in cleft. Cleft lined with gray matter, cortical surface at cleft often dysplastic/polymicrogyria
*******Identify 2 forms (and associated conditions)
SCHIZENCEPHALY
➤can be unilateral or bilateral. Bilateral often associated with mental retardation and spasticity, unilateral frequently associated with epilepsy, but not as often with significant other neurologic deficits.
Describe the following
- complete vs partial
- associated with?
- ➤agenesis/dysgenesis of corpus callosum frequent anomaly, wide variety of clinical symptoms.
- ➤complete or partial. Partial can be thinning of entire structure or absence caudal portion. Rostral portion usually retained unless complete agenesis present
- ➤can be associated with chiari II, disorders of neuronal migration
Identify septum pellucidum abnormality
➤Septum verum, which contains nerve cells, and septum pellucidum thin translucent plate forming medial wall of lateral ventricle. Development associated with corpus callous
➤Cavum septum pellucidum 20% of normals (BENIGN VARIANT)
➤absence of the septum pellucidum - primary agenesis, or secondary due to damage (hydrocephalus) Frequently associated with other abnormalities - septooptic dysplasia, agenesis of corpus callous, schizencephaly, hydrocephalus or encephaloceles.
Dandy walker spectrum phenotype
➤core criteria: cerebellar vermis hypoplasia/aplasia, cystic enlargement of 4th ventricle, elevation of roof of posterior fossa.
➤associated malformations include occipital encephalocele, polymicrogyria, heterotopias. 10 - 17% have agenesis or dysgenesis of corpus callosum
Describe the following
HOLOPROSENCEPHALY
- ➤about day 22 of gestation single prosencephalic vesicle forms at end of neural tube. By day 32 the telencephalon and diencephalon separate and the telencephalon divides into 2 separate hemispheres
- ➤Holoprosencephaly is characterized by failure of complete separation of the prosencephalon into distinct cerebral hemispheres and also separation of telencephalon from diencephalon.
- ➤incidence in live birth 1:10,000, but incidence in aborti is 1:250.
Describe the forms of holoprosencephaly acording to severity
- ➤alobar holoprosencephaly nearly complete lack of separation into hemispheres with single midline ventricle, often communicating with dorsal cyst. Interhemispheric fissure and corpus callosum are not present.
- ➤semilobar holoprosencephaly, anterior hemispheres not separated, but some degree of separation of posterior hemispheres. Splenium of corpus callosum is present. Frontal horns of lateral ventricles not developed but posterior horns are.
- ➤mildest form - lobar holoprosencephaly lacke of separation of most rostral and ventral components of hemispheres. Splenium and body of corpus callosum present, but genu absent. Rudimentary frontal horns may be present
- ➤middle hemispheric variant - midportion of cerebellar hemispheres is continuous, with absence of corpus callosum in this region, but separation of anterior frontal lobes, basal forebrain and occipital lobes.
Cortical development malformation
- ➤syndrome with enlargement of one side of brain with associated gyral malformations, cortical thickening with lack of lamination, blurred gray-white boundaries, abnormal cell types.
Hemimegalencephaly
- ➤some patients no more than half a hemisphere (hemi-hemimegalencephaly) more commonly posterior quadrant
- ➤isolate brain lesion but rarely associated with neurocutaneous syndromes
- ➤seizures usually in first 6 months of life, usually partial onset
- ➤can have infantile spasms. Some have hemi spasms (one sided spasms)
Identify neuronal migration malformation
- ➤thick cortex, 4 layers
- ➤can have agyria, or pachygyria
- ➤ventricles enlarged
- ➤associated with LIS1, DCX, and ARX
*****DCX gene causes what?
LISSENCEPHALY - Smooth brain
SUBCORTICAL BAND HETEROTOPIA
- ➤most common cause is DCX gene
- ➤usually seen in females, due to X-inactivation
- ➤males with this gene usually have lissencephaly, although males with band heterotopia are reported
Identify type of lissencephaly
➤3 overlapping syndromes, all genetic, autosomal recessive
- ➤Fukuyama’s congenital muscular dystrophy
- ➤muscle-brain-eye disease
- ➤Walker-Warburg syndrome
COBBLESTONE COMPLEX LISSENCEPHALY
- ➤cobblestone cortex, enlarged ventricles (may have hydrocephalus), abnormal white matter, small brainstem, small dysplastic cerebellum
- ➤cortex severely disorganized with no recognizable layers
- ➤groups of neurons in inappropriate location
- ➤most common is periventricular nodular heterotopias
- ➤if single or few symptoms such as seizures are common
- ➤if bilateral and many genetic basis likely
- ➤can be associated with hypoplasia of corpus callosum or cerebellum
- ➤has been associated with polymicrogyria
- ➤X-linked PNH due to mutation in Filamin-A gene (FLNA)
NEURONAL HETEROTOPIAS
HYDROCEPHALUS
- ➤obstructive, communicating
- ➤associated with congenital malformations, infections, neoplasms, bleeds/trauma, vascular malformations (vein of galen), variety of syndromes
- ➤X-linked hydrocephalus with aqueductal stenosis
- ➤obstructive may need shunt, VP most common
Hydranencephaly
***Most likely Vascular
- -Normal spinal cord, some brainstem and basal ganglia
- -Cortex is gone??
- -Normal differentiation but something happened in tissues and was lost? Most likely vascular problem
Charactericstics of what organism?
- no oxygen?
- gram stain
- motile?
- 2 toxins
CLOSTRIDIUM TETANI
- •obligately anaerobic bacillus
- •gram positive in fresh culture, variable in old culture
- •Can be flagellated and sluggish motile during growth
- •Produce 2 toxins:
- 1)Tetanospasmin (commonly called tetanus toxin) in toxigenic strains
- 2)Tetanolysin, uncertain importance
- •Mature organisms resemble a squash racquet
- •Spores are extremely stable, retaining the ability to germinate and cause disease indefinitely
- •Spores withstand exposure to ethanol, 5% phenol up to 10h, or formalin, heat stable
- •Spores rendered noninfectious by iodine, glutaraldehyde, hydrogen peroxide, or autoclaving at 121° C and 103 kPa (15 psi) for 15 minutes
- •Growth in culture under strictly anaerobic conditions (no diagnostic value)
- Spores of tetanus bacteria are everywhere in the environment, including soil, dust, and manure
- In general, the further the injury site is from the central nervous system, the longer the incubation period
- A shorter incubation period is associated with more severe disease, complications, and a higher chance of death (worse prognosis)
- In neonatal tetanus, symptoms usually appear from 4 to 14 days after birth, averaging about 7 days
- Common ways of entry: wounds contaminated, puncture wounds, burns, crush injury
- Rare ways of entry: surgeries, dental, IM or IV injections
Pathogenesis of Clostridium tetani
- •Spores enter the body (wound, needle, stump infection, etc.)
- •Anaerobic conditions, the spores germinate producing toxin during stationary phase which released when cell lysis
- •Toxin disseminated via blood stream and lymphatic system
- •Toxin acts at several sites CNS, sympathetic nervous system
- •Toxin blocks inhibitory transmitters release
- •Unopposed muscle contraction and spasm
- •Seizure, autonomic nervous system
- •Death from respiratory failure
- •The estimated minimum human lethal dose is 2.5 nanograms per kilogram of body weight.
Pathology of Ischemic stroke
Pathology of Hemorrhagic stroke
***Common sites
MRI showing low signal foci in cerebral amyloid angiopathy. Conventional gradient echo T2*-weighted image and susceptibility weighted image (SWI)
The 66 y/o male is evaluated and found to be globally aphasic. His eyes are deviated to the left and he does not move his right side spontaneously or to noxious stimulation. He does not blink to threat when approaching his right visual field. His NIH stroke scale was 26 (this is high).
Vitals: 167/90, 83, 16, 99% sats
Labs:
CBC: normal
BMP: Cr- 1.8 ( a bit elevated), Glucose 150.
PT/PTT/INR- normal
Imaging:
CT brain (noncontrast) and CTA head and neck (with contrast) are performed.
Left MCA Stroke
Hyperdensity on left side
Localization of stroke
**Differentiale left vs right hemisphere
•Left hemisphere; Cortical symptoms (MCA); visual defects, hemiparesis
•If it is right hemisphere (subcortical stroke); pure sensory or pure motor and NO CORTICAL LOCALIZATION AT ALL
Complication of TPA?
HEMORRHAGE
- Left side hemorrhage not much you can do
- If it was right side hemoorage; can do craniotomy
41 y/o male presents to the ED following two days of severe neck pain and now new onset vertigo and vomiting. History obtained from wife reveals he was normal with no past medical history. At the time of initial assessment he is too vertiginous to open his eyes and cooperate with examiner in the ED.
Neurology consulted for persistent vertigo and possible eye movement abnormality. Patient’s exam showed: torsional movement of eye with nystaagmus in all fields. Sensory deficit is mild. subject difficulty in swallowing. Weak on other side of body opposite side of face weakness
CT brain is normal
Wallenburg INFARCT – MEDULLAR INFARCT
- •Common cause of stroke in young people
- •Often happens after trauma, but can happen even without clear history
- •Vertebral artery clots and can lead to posterior circulation strokes, some can be very bad.
VERTEBRAL DISSECTION
56 y/o female comes to the ED complaining of abrupt onset severe slurring of speech, right facial weakness and mild clumsiness in her right hand. Past medical history is notable for hypertension, but she has not been taking her medications. No prior history of strokes, heart disease, diabetes, or high cholesterol. She does smoke 1ppd since she was 14 years of age.
CT Brain was normal in the ED.
Acute ischemic stroke
Identify
WATER SHED INFARCT (like between ACA and MCA or MCA and PCA)
•Patients that have an MI which leads to cardiogenic shock are more likely to develop areas and necrosis in the brain due to hypoxic-ischemic encephalopathy.
- –This is due to the decrease in BP associated with the cardiogenic shock. Profound hypotension causes global cerebral ischemia.
- –The areas of the brain that are most susceptible to ischemia are the pyramidal cells of the hippocampus and the Purkinje cells of the cerebellum. I
- –If ischemia is profound enough, the watershed areas are susceptible to infarction as well. These zones are the borders between areas perfused by the ACA, MCA, and PCA.
Identify stroke symptoms based on type of stroke
- ACA
- MCA
- PCA
- Subcortical lacunar infarct
- Basilar artery
- vertebral artery
Apraxia
- Apraxia is a disorder of the brain and nervous system in which a person is unable to perform tasks or movements when asked,
Alexia (inability to read) and Agraphia (inability to write)
- Alexia with Agraphia; o Alexia with agraphia most commonly occurs as part of an aphasia syndrome, but may rarely occur without aphasia.
Agnosia
o Agnosia is a loss of ability to recognize an entity for what it is- a percept stripped of its meanings
o Examples:
Finger agnosia: can’t recognize individual fingers
Anosognosia: can’t recognize that something is malfunctioning or is deficient (seen with hemi-neglect)
Asomatognosia: can’t recognize part of your body as part of you (seen with hemi-neglect)
Prosopagnosia: can’t recognize faces
Color agnosia: can’t recognize colors
Pure word deafness (verbal auditory agnosia): can’t recognize words
