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People with pneumococcal meningitis will be admitted to the hospital for immediate intravenous antibiotic treatment. Typically, doctors use an antibiotic called ceftriaxone to treat pneumococcal meningitis. Other antibiotics used include: penicillin, benzylpenicillin, cefotaxime, chloramphenicol, vancomycin (used if the antibiotic is not working and the provider suspects antibiotic resistance) 96 In some situations, doctors may also prescribe corticosteroids to help reduce swelling around the brain and spinal column. 94 Dexamethasone is also often used before antibiotics in cases of this disease, and improves outcomes. 97 In addition the patient is often put on an intravenous drip to give fluids, which stops them getting dehydrated and ensures the correct balance of sugars and other components in the blood. Even patients who respond quickly to treatment and are well enough to stay on a regular hospital ward will need a two-week course of intravenous antibiotics to cure pneumococcal meningitis. 95 Other than that I would also monitor and manage elevated intracranial pressure, and regularly assess clinical status, vital signs, and laboratory parameters.

- Bacterial meningitis - An extremely serious illness. Immediate medical help is needed. It can be life-threatening or lead to brain damage unless there is a quick treatment. Several kinds of bacteria can cause bacterial meningitis. The most common ones in the are: Group B Streptococcus 78 Streptococcus pneumoniae (pneumococcus) 77 - adults Neisseria meningitidis (meningococcus), - adults, N. meningitidis, causes meningococcal meningitis, is the one with the potential to produce large epidemics. There are 12 serogroups of N. meningitidis that have been identified, 6 of which (A, B, C, W, X , Y and Z) can cause epidemics. 76 Listeria monocytogenes (in older people, pregnant women, or those with immune system problems) 77 Escherichia coli (E. coli) 78 Haemophilus influenzae type b (Hib) bacteria - a common cause of meningitis in babies and young children until the Hib vaccine became available for infants. There are also vaccines for Neisseria meningitidis and Streptococcus pneumoniae. Experts recommend that all children get them, as well as all adults who are at a higher risk for the disease. 77 In many cases, bacterial meningitis starts when bacteria get into the bloodstream from the sinuses, ears, or throat. The bacteria travel through the bloodstream to the brain. The bacteria that cause meningitis can spread when people who are infected cough or sneeze.77 Serious bacterial infections can be effectively treated with antibiotics. These medicines either kill the bacteria or stop them multiplying. This helps the body’s immune system fight the bacteria. The choice of antibiotic will depend on the bacteria that is causing your infection. Antibiotics that work against a wide range of bacteria are called broad-spectrum antibiotics. Antibiotic resistance is a growing problem so antibiotics must always be used appropriately and as prescribed. 80 Not all bacterial infections need to be treated - some go away on their own. When you do need treatment, healthcare providers use antibiotics. Depending on where your infection is and how serious it is, antibiotics can be prescribed as: oral medication (pills), IV medication, given to you at a doctor’s office or hospital directly into a vein, ointment or cream, eye drops.81 Healthcare providers treat bacterial meningitis with antibiotics. They’ll give you an IV (intravenous) antibiotic with a corticosteroid to bring down the inflammation even before all the test results are in. 78 This helps to ensure recovery and reduce the risk of complications, such as brain swelling and seizures. 79 The antibiotic or combination of antibiotics depends on the type of bacteria causing the infection. Your health care provider may recommend a broad-spectrum antibiotic until the exact cause of the meningitis is known. 79 When the lab identifies the specific bacterium causing the condition, the provider may change to a different antibiotic. 78 The provider may drain any infected sinuses or mastoids - the bones behind the outer ear that connect to the middle ear. 79 - Malaria - This is the first diagnosis to exclude in any patient returning from an endemic region with a fever. Mosquito bites are often unnoticeable, and chemoprophylaxis and bite avoidance measures cannot provide 100% protection. The expected standard of investigation to exclude malaria is at least three negative malaria blood smears each taken 24 hours apart. There are several new rapid malaria detection tests available which are highly sensitive and specific. Malaria is caused by protozoan parasites of the genus Plasmodium, spread by female anopheline mosquitoes, which require a blood meal for egg development. Between 1–3 million people die from malaria each year. Most of these deaths occur in children, or in non immune adults, those living outside areas with high transmission, and are almost exclusively due to infection with Plasmodium falciparum. In areas of high transmission, immunity develops which does not prevent infection, but limits the severity of disease. This immunity is strain specific and is rapidly lost when a person leaves a hyperendemic region. Clinically, malaria is divided according to whether it is “uncomplicated” or “severe”. The features of uncomplicated malaria are common to all four infecting species. The syndrome consists of a prodromal period of lassitude, headache, muscle aches and vague abdominal pain, followed 2–8 hours later with fever: similar symptoms to the common cold or flu. Rigors may occur. With prompt presentation and treatment it is unusual to see the classical patterns of two or three day intermittent fevers developing. Hepatosplenomegaly and anaemia may develop as the infection progresses and pronounced diarrhoea, constipation, and even a dry cough may occur. The neurologist is more likely to be involved in the care of patients with severe or complicated malaria, which is always due to P falciparum. Severe malaria is defined according to World Health Organization (WHO) criteria, last updated in 2000. Neurologists may also be involved in the care of patients with the post-malaria neurological syndromes - relatively rare conditions where neurological symptoms develop after successful parasite clearance. Cerebral malaria - Is the most obvious feature of severe malaria and is strictly defined as unrousable coma, but in practice any impairment of conscious level should be considered concerning. It is uniformly fatal in the absence of treatment and the overall mortality of treated cerebral malaria is around 20% in adults. The prodromal illness usually lasts a few days, but can be much shorter in children. However, it is possible to have lethal malaria infection with no impairment of consciousness until death. Many neurological symptoms and signs have been described in severe malaria, including meningism, fits, focal neurological signs, and oculogyric crisis. However, these are rare, and the most common manifestation is that of a symmetrical encephalopathy with no focal neurological signs. Careful examination of eye movements should be performed to exclude subtle seizure activity. A number of abnormalities on fundoscopy have been described, including cotton wool spots, haemorrhages, and papilloedema (less common in adults). Gaze may be divergent but cranial nerve lesions are unusual. Tone and reflexes may be increased, normal or depressed, and abdominal reflexes are often absent. There may be decorticate or decerebrate posturing and opisthotonus. Deep coma, extensor posturing, seizure activity, respiratory distress, hypoglycaemia, hyperlactataemia, and a high parasite load > 4% (that is, more than 4% of all red blood cells parasitised) are poor prognostic signs. Laboratory findings in severe malaria can include a normocytic normochromic anaemia, thrombocytopenia, normal or low white cell count, and evidence of disseminated intravascular coagulation. Hypoglycaemia occurs as a direct consequence of infection or as a side effect of intravenous quinine treatment, and should be excluded in an unconscious patient or anyone that deteriorates following admission. Hyponatraemia, raised urea and creatinine values, and raised blood lactate may occur. Lumbar puncture may reveal elevated pressure in children, but is usually normal in adults. The cerebrospinal fluid (CSF) is usually normal in cerebral malaria but there may be an elevated protein or mild lymphocytosis. CSF lactate may be raised and glucose may be slightly low. With treatement it is important to exclude hypoglycaemia and underlying seizure activity in any unconscious patient with malaria. In the last 10 years there has been a dramatic increase in the incidence and global spread of drug resistance and in many parts of the world P falciparum is now completely resistant to chloroquine. Treatment options are therefore limited and the mainstay of treatment for severe malaria in the UK is intravenous infusion of quinine followed by a second drug, usually doxycycline. The most important side effect of quinine is hypoglycaemia, but tinnitus, deafness, and nausea (cinchonism), and rarely cardiac arrhythmias, can occur. Treatment of cerebral malaria is a medical emergency and specialist advice should be sought. Fits are common in cerebral malaria, particularly in children. Phenobarbitone reduces fits in cerebral malaria, but trials in Kenya demonstrated an increase in mortality in children receiving a single prophylactic injection. This may have been related to respiratory depression. The safety of other anticonvulsants such as phenytoin in the setting of severe malaria has not been determined. Corticosteroids are not beneficial in the treatment of cerebral malaria. Post-malaria neurological syndromes - Up to 3% of adults and 20% of children have a persistent neurological deficit after cerebral malaria. In children this appears to be related to the length of coma, profound anaemia, and prolonged seizures. Deficits include hemiparesis, cortical blindness, tremor and isolated cranial nerve palsies. Post-malaria neurological syndromes (PMNS) have been described in patients who appear to have recovered from their malarial illness but develop a new neurological syndrome a few days or weeks after becoming aparasitaemic. These problems can include acute confusional states, psychosis, generalised convulsions, tremor, or ataxia. PMNS is a relatively rare condition and usually follows severe malaria, but can follow uncomplicated disease and has been associated with the use of mefloquine, although it can occur in patients who have been treated with other drugs. This has led to the recommendation that mefloquine should not be used in the treatment of cerebral malaria unless there is no alternative available. The symptoms are distressing but generally short lived (ranging from a few hours to 10 days). There is also a syndrome of cerebellar ataxia occurring after malaria with symptoms continuing for a few weeks. Mostly these are self-limiting conditions that may have an autoimmune post infectious aetiology. There is no trial evidence of benefit from treatment with corticosteroids. Typhoid - a systemic infection characterised by high fever, headache, and clouding of consciousness. It is caused by Salmonella typhi. Salmonella paratyphi can cause a similar although usually less severe syndrome, and has a shorter incubation period. Up to 300 cases of typhoid are imported to the UK each year, the majority originating from South Asia. The mortality of untreated typhoid is around 20%. With appropriate treatment this falls to less than 1%. The duration of illness is usually about four weeks. Despite common misconceptions, diarrhoea occurs in only about 40% of people with typhoid; 20% have normal bowel habit and 40% are constipated. An initial high fever, headache, malaise, and occasionally dry cough may be followed by abdominal distension, splenomegaly, and rose spots (difficult to see in dark skinned patients) in the second week. Untreated, the patient may develop a pronounced confusional state and complications occur: these include intestinal perforation or abscess formation in sites such as the heart, bones, joints, pleural space, or gall bladder. Sudden and massive intestinal haemorrhage may be life threatening. Meningitis or cerebral abscess may occur. Typhoid may present to the neurologist early in the disease because of an acute confusional state or fits. Later and rarer neurological complications include transverse myelitis, polyneuropathy, cranial mononeuropathy, and demyelinating leucoencephalopathy. Diagnosis is made through isolation of the organism from blood, stool, urine or bone marrow cultures, and treatment is with quinolone antibiotics guided by antibiotic sensitivity testing and knowledge of the resistance patterns in the country where the infection was acquired. HIV - Travellers are at increased risk of all sexually transmitted infections. There were over 4200 new diagnoses of HIV infection made in the UK in 2002. Over half of these were in heterosexuals, many having acquired their infection in sub-Saharan Africa. The many different presenting syndromes can be caused by HIV itself, or by opportunistic infection as a result of immunosuppression in established HIV infection. HIV should be considered in the differential diagnosis usually all the time. Encephalopathy complicates 6% of all HIV seroconversion illnesses, and a further 6% will develop neuropathy as part of primary infection. There is a clear benefit from starting anti-retroviral therapy before there is severe immunosuppression (CD4 ⩽ 200 cells/ml), and there may be a benefit in treating acute seroconversion syndromes in preserving HIV-specific cytotoxic T cell responses, so it is vitally important to diagnose HIV infection if present. Other neurological syndromes described as part of primary HIV infection include: retro-orbital pain increased with eye movement, myelopathy, brachial neuritis, facial palsy, cauda equina, and Guillan-Barre syndromes. Encephalitis (Arboviruses) - There are many arthropod borne viruses capable of causing encephalitis. Arboviruses are major causes of encephalitis worldwide, but Japanese encephalitis (JE) virus is probably responsible for more cases of acute encephalitis than all the other arboviruses combined. JE virus appears to be expanding outward from southern China and Southeast Asia and is reaching Russia, the Philippines, Pakistan, and Australia. Depending upon the climate, disease can be transmitted seasonally or year round. Most cases are asymptomatic, but of those with clinically apparent disease 30% will die and 50% will be left with neurological deficit. Treatment is supportive, but an effective vaccine is available. West Nile virus is also increasing its geographical range. Originally confined to Africa and the Middle East, it has caused sporadic cases in humans and horses in Europe. There is evidence of seropositivity among British birds, but no evidence of disease in the UK yet. A vaccine for tick borne encephalitis is available for hikers/campers travelling to Scandinavia and central Europe. 100 Tick-borne encephalitis (TBE) virus is spread through the bite of an infected tick. Occasionally, TBE virus can spread to people through eating or drinking raw milk or cheese from infected goats, sheep, or cows. TBE virus can be found in parts of the region stretching from western and northern Europe through northern and eastern Asia. People who travel to these areas might be at risk for infection. TBE virus is not found in the United States. The ticks that spread TBE virus are most active in warmer months (April through November). People who spend time outdoors in or near forests are at highest risk of being bitten by a tick infected with TBE virus. 99 Encephalitis (Enteroviruses) - Polio is the most notable enterovirus to cause neurological disease. It appears to have been eradicated from the Americas, and the WHO anticipates global eradication by 2005. Other enteroviruses cause seasonal meningitis and meningoencephalitis, often in children. There was a large outbreak of enterovirus 71 infection in children in Taiwan in 1998, in which there were a large number of neurological complications with a death rate approaching 20%. Patients typically had myoclonus, ataxia, and cranial nerve involvement. Currently, treatment is supportive, but pleconaril is a new anti enteroviral drug currently undergoing evaluation. Japanese encephalitis (and other flaviviruses such as West Nile virus, tick-borne encephalitis can present with a syndrome clinically very similar to polio. Rabies - universally fatal once symptoms become apparent. Infection is caused by viruses of the genus Lyssavirus, usually following a bite from a warm-blooded animal. Different animals have different susceptibilities to infection - foxes and coyotes appear most susceptible, while the opossum seems relatively protected. Most human cases are caused by dog bites, but infection can result from apparently trivial contact with bats and other animals. European bat lyssa viruses, which are closely related to the rabies virus, can cause a rabies like illness in humans. Volunteer and licensed bat handlers should be vaccinated against rabies. Following a bite or scratch (or perhaps inhalation of bat respiratory secretions), there is a variable incubation period, usually between 20–90 days, before the development of prodromal symptoms. An incubation period of 19 years has been reported. Forty percent of patients describe itching or parasthesiae at the healed injury site, and constitutional symptoms include fever, headache, myalgia, and gastrointestinal upset. Over the next few days, progression to one of two syndromes - furious or paralytic rabies occurs. The former is most common and is characterised by hydrophobic spasms, excitation, aggression, and hallucinations interspersed with periods of calm. There may be opisthotonus and generalised convulsions, arrhythmias, respiratory disturbance, cranial nerve lesions, and autonomic dysfunction. Eventually there is coma, paralysis, and death. Paralytic rabies is characteristic of bat transmitted rabies. Following the prodrome, there is paraesthesia and ascending flaccid paralysis starting from the injury site. There is loss of tendon and plantar reflexes, but sensation is intact. Death occurs after 1–3 weeks. Treatment consists of good wound toilet and post-exposure immunoglobulin and post-exposure vaccination for those suffering animal bites or scratches. This is extremely effective if given before the development of clinical disease. For established disease, treatment consists of symptom control through sedation. Although admission to intensive care can extend life for weeks and sometimes months, treatment with hyperimmune serum and antiviral drugs has not been effective and death is inevitable. In wealthy countries rabies vaccine is produced from cell culture lines. In less wealthy countries it is sometimes derived from neural tissue, and there is a risk of a post-vaccinal encephalomyelitis which has similar symptoms to paralytic rabies. The incubation period is two weeks to two months. Conventional treatment includes corticosteroids. A fifth of cases are fatal, but if recovery occurs it is usually complete. African trypanosomiasis - (sleeping sickness) is caused by subspecies of the protozoan Trypanosoma brucei—T b gambiense (West African sleeping sickness, WASS) and T b rhodesiense (East African sleeping sickness, EASS). There has been a notable increase in the prevalence of this disease since the 1980s, and WHO estimates up to 600 000 people are currently infected. There have been clusters of infection of EASS among tourists visiting game parks. The disease is universally fatal if untreated and occurs in localized pockets. It is spread by the painful bite of the Tsetse fly. EASS and WASS differ in their epidemiology and clinical presentation. EASS is a zoonosis, with cattle forming the main reservoir. Humans are the major reservoir in WASS. Disease progression is more rapid in EASS, with death occurring within a few weeks compared with months to years in WASS. East African sleeping sickness - The first stage of the disease develops 5–15 days after the infective bite. There may be a chancre at the site of the bite, but this painful, well circumscribed papule is often not seen in Africans. Local lymphadenopathy may develop, and fever accompanies the waves of parasitaemia. Invasion of the central nervous system leads to the second stage of disease—a progressive chronic meningoencephalitis leading to death 6–9 months after the initial bite. Drowsiness is the prominent feature—focal neurological signs are less common than in WASS. West African sleeping sickness - Incubation is 2–3 weeks, but chancres are uncommon. There is usually an irregular fever, but other symptoms may be absent. Winterbottom’s sign (enlarged posterior cervical lymph nodes) is seen in up to 85% of patients. The asymptomatic period that follows may last for several years and parasites may be difficult to find within the blood. Signs of second-stage (central nervous system) infection include motor problems, speech disturbance, or a syndrome resembling Parkinsonism. Patients may suffer personality changes or psychosis; changes in sleep patterns precede apathy, coma, and death. Most neurological signs reverse with treatment. Diagnosis is made through the demonstration of parasites in the blood or lymph node aspirates. Blood concentration methods improve detection of parasites and immunological tests are available for the diagnosis of WASS. Treatment depends upon the stage of the disease. CSF should always be examined for parasites, although one or two doses of treatment are normally given before lumbar puncture to clear parasites from the blood and prevent inadvertent inoculation into the CSF. A CSF leucocyte count of > 5 cells/ml is considered evidence of second-stage disease, whether or not parasites are seen. The treatment for sleeping sickness has significant toxic effects. First-stage WASS can be treated with pentamidine. Suramin is used for EASS. Second-stage WASS is treated with eflornithine, while EASS is treated with melarsoprol, which causes an encephalopathic syndrome with 50% mortality in 10% of patients. Herpes B virus - This simian herpes virus is enzootic in macaques, with 80–90% of macaques being infected. It is the equivalent of herpes simplex virus in humans, causing lifelong infection with intermittent viral shedding, and is the only simian herpes virus known to cause infection in humans. Macaque handlers and travelers who are bitten or scratched by monkeys are at risk, although human infection is rare. The incubation period in humans is typically 2–10 days, but intervals of up to 10 years between exposure and illness may represent reactivation of latent infection. A herpetiform rash may develop at the site of a bite or scratch, accompanied by fever and malaise. An ascending paralysis develops over the following 1–2 weeks, which then leads to pan-encephalitis. Diagnosis can be made by polymerase chain reaction (PCR) of CSF. Mortality is high at around 60%. Therapeutic experience is limited but intravenous acyclovir is recommended, as is post-exposure acyclovir prophylaxis for those suffering bites or scratches. Cryptococcal meningitis - Cryptococcus neoformans has achieved prominence as the second leading cause of death in HIV-positive patients worldwide. In the tropics, particularly northern Australia and Papua New Guinea, there is a variety of C neoformans that affects the immunocompetent (C neoformans var gattii). There is commonly concomitant pulmonary disease. In the environment, it is found in close association with the eucalyptus tree, and koala bears are also affected. Treatment is similar to treatment for HIV-associated disease, although there may be a role for steroids. Permanent neurological deficit, particularly blindness, is common and the mortality rate is high. Eosinophilic meningitis - There are many causes of this syndrome. In travelers to Africa, schistosomiasis is the most common helminth infection encountered. Very rarely, eosinophilic meningitis may result from the presence of ectopic eggs; this requires prolonged infection and a relatively heavy worm burden and is therefore rare in the tourist. Ectopic deposition of eggs in schistosomiasis can also cause spinal syndromes. The risk of eosinophilic meningitis is greater for the traveler to Southeast Asia, where the justifiably famous cuisine may include raw or pickled snails, amphibians, or snakes. The cautious take a phrase book into the restaurants. It is relatively easy to kill the worms with antiparasitic drugs. However, the physical damage caused by the infection may result in severe neurological deficits. Steroids are recommended as adjuvant treatment.100 Meningococcal meningitis – Is caused by the bacteria Neisseria meningitidis, which infects the lining of the brain and spinal cord and causes swelling. 101 Tuberculous meningitis - manifests extrapulmonary tuberculosis caused by the seeding of the meninges with the bacilli of Mycobacterium tuberculosis (MTB). MTB is first introduced into the host by droplet inhalation infecting the alveolar macrophage. The primary infection localizes in the lung with dissemination to the lymph nodes. At this point in the infectious process, a high degree of bacteremia can seed the entire body. In tuberculous meningitis, the meninges are seeded by MTB and form sub-ependymal collections called Rich foci. These foci can rupture into the subarachnoid space and cause an intense inflammatory response that causes meningitis symptoms. The exudates caused by this response can encase cranial nerves and cause nerve palsies. They can entrap blood vessels causing vasculitis, and block cerebral spinal fluid (CSF) flow leading to hydrocephalus. These immune responses can lead to complications associated with tuberculous meningitis and chronic sequela in patients who recover from TBM. This activity reviews evaluation, management, and current public health preventative measures to prevent tuberculous meningitis. This activity highlights the interprofessional teams involved in preventing and managing this global health threat. 102 Neurocysticercosis - Cysticercosis is a parasitic infection that results from ingestion of eggs from the adult tapeworm, Taenia solium (T. solium). When cysticercosis involves the central nervous system, it is called neurocysticercosis. Neurocysticercosis is the most common parasitic infection of the brain and a leading cause of epilepsy in the developing world, especially Latin America, India, Africa, and China. 103 Listeriosis - Listeria infection is a foodborne bacterial illness that can be very serious for pregnant women, people older than 65 and people with weakened immune systems. It's most commonly caused by eating improperly processed deli meats and unpasteurized milk products. Healthy people rarely become ill from listeria infection, but the disease can be fatal to unborn babies, newborns and people with weakened immune systems. Prompt antibiotic treatment can help curb the effects of listeria infection. Listeria bacteria can survive refrigeration and even freezing. So people who are at higher risk of serious infections should avoid eating the types of food most likely to contain listeria bacteria. 104 Brucellosis - Brucellosis is a bacterial infection that spreads from animals to people. Most commonly, people are infected by eating raw or unpasteurized dairy products. Sometimes, the bacteria that cause brucellosis can spread through the air or through direct contact with infected animals. Signs and symptoms of brucellosis may include fever, joint pain and fatigue. The infection can usually be treated with antibiotics. However, treatment takes several weeks to months, and the infection can recur. Brucellosis affects hundreds of thousands of people and animals worldwide. Avoiding raw dairy products and taking precautions when working with animals or in a laboratory can help prevent brucellosis. 105 Leptospirosis - Leptospirosis is a bacterial infectious disease that affects humans and animals. It is caused by bacteria of the genus Leptospira. In humans, it can cause a wide range of symptoms, some of which may be mistaken for other diseases. Some infected persons, however, may have no symptoms at all.Without treatment, Leptospirosis can lead to kidney damage, meningitis (inflammation of the membrane around the brain and spinal cord), liver failure, respiratory distress, and even death. 37

Normal : urea, electrolytes, liver function tests, glucose, erythrocyte sedimentation rate, C - C-reactive protein Abnormal : White cell count (18× 10 9 /L) - elevated = high white blood cell count, can indicate a range of conditions, including infections, inflammation, injury and immune system disorders. 82 Predominant neutrophilia - Neutrophilia, also known as neutrophilic leukocytosis, occurs when your neutrophil count is too high, which is often the result of a bacterial infection. To combat the infection, immature neutrophils leave your bone marrow too soon and enter into your bloodstream. 87 Opening pressure of 32 cmCSF (<20 cmCSF) – elevated, the normal range of ICP measured by LP in adults in a typical clinical setting should now be regarded as 6 to 25 cmH2O (95% confidence intervals), with a population mean of about 18 cmH2O 83 Turbid CSF – CSF is normally a clear fluid, this suggests the presence of cells, debris, or infection. 84 3200 white cells/mm 3 (85% neutrophils) – elevated, normal cerebrospinal fluid (CSF) in adults and children contains no more than 5 white blood cells (WBCs)/mm3. 86 200 red cells/mm 3 – elevated, normally, there are no RBCs in the cerebrospinal fluid, and there should be no more than five WBCs per cubic millimeter of CSF. If your fluid contains RBCs, this may indicate bleeding. 88 protein of 2.3 g/L (<0.45 g/L) – elevated, the normal CSF protein concentration ranges from 0.23 to 0.38 g/L in adults. 89 CSF glucose of 1.2 mmol/L (serum glucose of 6.0 mmol/L) – low, The glucose level in the CSF should be 50 to 80 mg/100 mL or 2.77 to 4.44 mmol/L (or greater than 2/3 of the blood sugar level). 90 Gram-positive cocci – indicate bacterial infection In Gram staining of the CSF, Gram positive diplococci or cocci in chains suggest Streptococcus pneumoniae, Streptococcus spp., Enterococcus spp., or other Gram-positives including Lactococcus. 85 A sample was sent for polymerase chain reaction studies, including for Pneumococcus – can come back positive, the clinical presentation, including the elevated white cell count with predominant neutrophilia, gram-positive cocci in the CSF, and turbid appearance, is consistent with pneumococcal meningitis. 92 Meningococcus – can come back positive, given the clinical presentation with gram positive cocci and the possibility of bacterial meningitis. 93 Both pneumococcus and meningococcus are bacteria that could cause meningitis and they fit all the findings in CSF. I would possibly lean more towards pneumococcus, because it is a common cause of bacterial meningitis, especially in adults. herpes simplex 1 and 2 – will probably come negative (there were Gram-positive cocci in the CSF) Ebstein–Barr virus – will probably come negative (there were Gram-positive cocci in the CSF) varicella-zoster virus – will probably come negative (there were Gram-positive cocci in the CSF) cytomegalovirus – will probably come negative (there were Gram-positive cocci in the CSF) tuberculosis. – more likely to come back negative as presentation with gram-positive cocci and elevated white cell count is more indicative of bacterial rather than mycobacterial infection. 91 The elevated white cell count, predominantly neutrophils, along with turbid appearance and elevated protein, is indicative of an inflammatory response in the central nervous system. The presence of gram-positive cocci suggests a bacterial etiology. The opening pressure is elevated, indicating increased intracranial pressure. The PCR studies are performed to identify the specific infectious agent responsible for the meningitis. Potential Diagnosis is bacterial meningitis: The gram-positive cocci and elevated white cell count with neutrophil predominance are consistent with bacterial infection. The specific causative agent would be determined by the results of the PCR studies.

- Key management points in patients with fever and altered mental status, rapid decisions need to be made regarding indicated diagnostic studies and therapeutic interventions. All patients should undergo emergent lumbar puncture if it is not contraindicated by the risk of brain herniation. CT scan of the brain before lumbar puncture should be performed in certain situations to attempt to assess intracranial pressure and the risk of herniation with lumbar puncture. When bacterial meningitis is suspected, empiric antibiotics should be given promptly and should not be delayed while awaiting the completion or results of diagnostic studies. Blood cultures should be performed before infusing antibiotics if possible. Empiric corticosteroids are also indicated in acute bacterial meningitis when the pathogen is unknown or suspected to be pneumococcus. When HSV encephalitis is suspected on clinical grounds, empiric high-dose acyclovir is also indicated. When a patient with suspected bacterial meningitis has either depressed mental status or focal neurologic deficit, an emergent CT scan of the brain is indicated to assess intracranial pressure and risk for brain herniation with lumbar puncture. CT scan does not always adequately rule out elevated intracranial pressure in the case of severe bacterial meningitis (primarily when due to pneumococcus but occasionally when due to other pathogens such as Group B streptococcus), and in this situation, specific intracranial pressure monitoring and the placement of an extraventricular device should be discussed. Though MRI findings can help detect meningitis, in this acute setting MRI is too time-consuming to be practical. If bacterial meningitis is suspected due to the presence of clinical findings noted above, rapid initiation of empiric antibiotic therapy to cover potential pathogens should be initiated. The use of corticosteroids adjunctively is associated with decreased morbidity (such as subsequent neurologic sequelae) and in some cases mortality with bacterial meningitis. Therefore, steroids should be given concomitantly or before empiric antibiotics. If bacterial meningitis is not determined to be present, the steroid therapy and antibiotic therapy can be discontinued. Emergency management's main goal is to focus on stabilizing the patient. If a patient’s consciousness is so depressed that he or she is unarousable or unable to produce a gag reflex, emergent intubation for airway protection and the prevention of massive aspiration is appropriate. If a patient is hemodynamically unstable, which can occur in the case of concomitant bacteremia and meningitis (such as with meningococcemia), measures should be undertaken to treat the patient’s septic shock with antibiotic therapy, high-volume infusions of intravenous fluids (though central catheters and wide-bored peripheral intravenous lines) and vasopressive agents. Empiric antibiotics for presumed bacterial meningitis should not be delayed while awaiting diagnostic studies such as a lumbar puncture. CT scan before lumbar puncture should be performed in patients with moderate to severely depressed mental status or focal deficits. Lumbar puncture is important in diagnosing bacterial meningitis and distinguishing it from other serious CNS infections such as HSV encephalitis and less severe infections such as enteroviral meningitis. In patients with worrisome clinical signs such as worsening consciousness (GCS <=11), papilledema, signs of brainstem pathology including changed pupillary reflexes, posturing and irregular respirations, and acute seizure, CT scan can rarely underappreciate the risk for herniation, and when clinical signs are present that could signal “impending” herniation, LP should be delayed and measures (such as IV mannitol and emergent neurosurgical consultation) should be undertaken to reduce intracranial pressure. The choice of empiric antibiotic therapy for bacterial meningitis and viral encephalitis should be guided in part by local resistance patterns and the likelihood of a given patient being infected with a given pathogen. Reasonable is to give broad empiric therapy when a specific microbiologic diagnosis is not yet known, recognizing that once more data are present, a tailored regimen can be constructed. Before CSF Gram stain, blood culture or HSV PCR data are available, treatment of pneumococcus, meningococcus and in some cases Listeria should be instituted empirically. When viral encephalitis is a concern, given HSV is generally the most common pathogen and is treatable, empiric high-dose acyclovir should be initiated. In the rare case where there is a known recent freshwater exposure, amoebic encephalitis should be considered and CSF should be specifically examined cytologically to visualize organisms. Clinical trials using dexamethasone in adults with bacterial meningitis have demonstrated clinical benefits, and therefore dexamethasone should be given with or before the empiric antibiotic therapy. Initial diagnostic and management points that should not be missed are: Initial stabilization of the patient - airway protected, intubation if indicated, hemodynamically stabilized, the goal is normovolemia. Neurologic examination - assess consciousness and mental status, assess GCS, cranial nerve exam including examination of optic discs for papilledema, pupillary reflex, gag reflex, motor, sensory, reflexes, coordination, meningismus Physical exam. Blood cultures. Lab work - CBC/coagulation profile for evidence of DIC, bleeding risk, [Na+] for evidence of SIADH or cerebral salt wasting, renal function, liver function testing. Intravenous line Institute antibiotic therapy and steroid therapy Determine if CT scan indicated CT : evidence of elevated ICP - neurosurgical consultation –>May require ICP monitoring, determine if IV mannitol, diuresis, hyperventilation indicated to manage elevated ICP. CT: evidence of hydrocephalus - neurosurgical consultation –> may require ventriculostomy. CT scan not indicated or demonstrating no evidence of asymmetry or impending herniation, Lumbar puncture 12. Determine if intravenous acyclovir indicated based on clinical history and initial CSF indices. 74 Early recognition and response by health professionals to patients whose physiological condition is acutely deteriorating is fundamental for safe and high-quality care, ensuring patients’ optimal outcomes. A timely, effective, and appropriate response may result in minimal intervention to stabilize the patient. Prompt, efficient, and adequate response to patients reduces mortality, cardiac arrests, and hospital or ICU length of stay. Key elements regarding recognizing clinical deterioration, include Primary Survey (ABCDE approached assessment), Full Vital Signs, and Early Warning Signs. Early detection and intervention for clinical deterioration in a patient are critical, and they can be accomplished by implementing appropriate skills. ABCDE assessment - The mnemonic stands for airway, breathing, circulation, disability, and exposure. The ABCDE (Primary Survey) approach is a useful clinical tool for the initial assessment of rapidly deteriorating patients in an acute clinical setting. It has been designed to ensure that life-threatening conditions are identified and treated early and that there is an order of priority. If a problem is discovered as this clinical pathway is being implemented, the problem must be addressed immediately before moving on to the next part of the assessment. The structured ABCDE approach outlines each component that needs to be assessed briefly, which includes a patient’s airway and cervical spine stabilization, breathing, and ventilation, circulation with hemorrhage control, disability (neurological status), and exposure and temperature control. The outcome of the assessment generates a general impression about the seriousness of the patient’s situation and how they are or may be affected. During the assessment, by looking, listening, and feeling, all the actual and imminent life-threatening risks, injuries, or illnesses, such as obstructed airways, fractures, brain injuries, hemorrhage, tamponade, and so forth, need to be identified, treated, or eliminated and stabilized immediately to prevent further deterioration. At the end of the primary survey, the patient is completely exposed to a warm environment to ensure that there are no immediate life threatening injuries that have been missed for intervention, as well as to be prepared to proceed to a secondary survey. A – Airway assessment - Is the airway patent? A primary survey begins by assessing and maintaining the patient’s airway, including checking airway patency, looking for obstructions and neck injuries, and if indicated, providing cervical spine protection. Untreated, airway obstruction causes hypoxia and risks damage to the brain, kidneys, and heart, as well as cardiac arrest and death. This involves three steps: Look - If the patient can speak normally, move on to assessing the other ABCDEs. If the patient is unable to talk, look for airway obstruction (partial or full), symmetrical chest wall movement, or use of any accessory muscle such as abdominal movement, Listen and Feel - listen and feel for airflow at the mouth and nose. B – Breathing - Is the breathing sufficiently maintained? This step is to assess the patient for any life-threatening respiratory conditions, exposing the chest and looking for signs of injury, measuring respiratory rate and oxygen saturation, and assessing work of breathing and chest expansion. This involves three steps: Look - Observe symmetrical chest wall movement for any abnormalities, increased work of breathing, including the use of accessory muscles (neck and shoulders), nasal flaring, any signs of central cyanosis, and rate/depth of respiration, Listen -Does the patient speak in a short sentence? Auscultate the chest wall to detect any abnormal breath sounds such as wheezing, crackles, or stridor and to check for the absence of breath sounds, Feel - Feel the chest wall for surgical emphysema (possible indication of pneumothorax); the trachea alignment due to deviation suggests tension pneumothorax. C – Circulation - Is the circulatory volume sufficient? It aims to control any external bleeding and identify any signs of hypovolemia from severe blood or fluid loss and shock by assessing heart rate and rhythm, blood pressure, and peripheral circulation. This involves three steps: Look - Look for signs of bleeding and poor circulation, such as pale or mottled skin, Listen (Pay attention) - Does the patient appear confused? Does the patient have chest pain? These could indicate poor perfusion to the brain and heart due to decreased circulatory volume, Feel - Feel for signs of poor perfusions, such as cool, moist extremities, delayed capillary refill, diaphoresis, low blood pressure, tachypnoea, tachycardia, absent pulses, and low urine output. D – Disability - What is the consciousness level? A quick evaluation of the patient’s conscious state and neurological function is performed as part of the evaluation of disability. Common causes of unconsciousness include profound hypoxia, hypercapnia, cerebral hypoperfusion, and the recent administration of sedatives or analgesics. During this phase, the patient’s blood glucose level should be checked to detect hypo- or hyperglycemia, which may contribute to altered mental status. Utilizing the ACVPU scale will facilitate a rapid assessment of the patient’s level of consciousness, which will be followed by an assessment of the patient’s pupils (size, regularity, and responsiveness to light) and limb movement. Use the Glasgow Coma Scale if a more comprehensive assessment of the patient’s level of consciousness is required. The ACVPU scale measures a patient’s level of consciousness: A – the patient is alert, C - new confusion or delirium, V – the patient is responding to verbal commands, P - the patient responds to a painful stimulus, U – the patient is unresponsive E – Exposure - Are there any other causes for the patient’s deterioration? The purpose of this is to investigate any clues that might explain the patient’s condition: It involves removing all of the patient’s clothing to inspect their body for any additional and potentially life threatening injuries such as bleeding, rashes, bites, or other lesions, followed by promptly warming and maintaining control of the patient’s temperature. To successfully recognise and respond to acute physiological decline, plans for monitoring vital signs and providing continuous patient care must be developed and communicated. Vital signs are a useful tool to identify patients who are at risk of deterioration because abnormal values in vital signs such as blood pressure (hypertension/hypotension), respiratory rate (tachypnoea/apnoea), heart rate (tachycardia/bradycardia), and low oxygen saturation often indicate patient deterioration before the occurrence of these serious adverse events. To improve recognition of physiological abnormalities indicating deterioration, monitoring plans should at the very least include an assessment of the elements below and documentation in a structured tool. The elements are: Respiratory rate: Compare RR to previous measurements and search for deteriorating trends (Hyperventilation or Hypoventilation). Oxygen saturation: Compare the oxygen saturation level to previous measurements and search for deteriorating patterns (Hypoxia). Heart rate: Examine heart rate, compare with previous data, and search for deteriorating tendencies. If there are variations, how does the heart rate deviate from the usual heart rate? (Tachycardia or Bradycardia) Blood pressure: Compare blood pressure with previous values and search for deteriorating trends (Hypertension or Hypotension). Temperature: Check the temperature and compare it to previous measurements. Look for deteriorating trends (Hyperthermia or Hypothermia). Level of consciousness: Utilise A.V.P.U. (Alert, responds to Voice or Pain, Unconscious) to evaluate the patient’s mental status and any new-onset disorientation or behavioral change. An increase in RR (Respiratory Rate) can usually be seen a few hours prior to a change in the other vital signs. As a result, even minor changes in RR can be a sign of a patient’s deterioration. Studies have shown that changes in a patient’s respiratory rate are reliable and predictive indicators of clinical deterioration in both adult and pediatric patients. As the body attempts to maintain homeostasis by delivering oxygen to organs and tissues, a deviation in respiratory rate can be the first sign of deterioration and an early indicator of physiological conditions that cause clinical deterioration such as hypoxia, hypercapnia, metabolic and respiratory acidosis. 75 Early warning systems, commonly referred to as ‘track and trigger’ systems, are systematic processes that measure fundamental vital signs and respond to the results. When a predetermined criterion (the trigger) is met, an action should be taken. Many early warning systems rely on routine physiological monitoring, including vital signs. The calling criteria for a medical emergency team (MET) are one of the most common types of single parameter systems in Australia: With periodic monitoring of selected vital signs against a simple set of predefined criteria, with a response algorithm activated when any criterion is met. Airway - Partial airway obstruction (excluding snoring) =>Early warning signs of patient deterioration, Airway obstruction or stridor => Late warning signs of patient deterioration Oxygen Saturation - SaO2 90–95%=>Early warning signs of patient deterioration, SaO2 < 90%=> Late warning signs of patient Respiratory rate - 5–9 or 30–40/min =>Early warning signs of patient deterioration, < 5 bpm or > 40/min => Late warning signs of patient deterioration Heart rate - 40–50 bpm or 120–140bpm => Early warning signs of patient deterioration, < 40 bpm or >140bpm => Late warning signs of patient deterioration Blood pressure - Systolic BP 80–100 mmHg or 180–240 mmHg => Early warning signs of patient deterioration, Systolic BP < 80 mmHg or > 240 mmHg => Late warning signs of patient deterioration Urine output - < 200 mL over eight hours => Early warning signs of patient deterioration, < 200 mL in 24 hours or anuria => Late warning signs of patient deterioration Drainage output - Greater than expected drainage fluid loss => Early warning signs of patient deterioration, Excess blood loss not controlled by ward staff => Late warning signs of patient deterioration Mental status - A drop in GCS of 2 points or GCS < 12 or any seizure loss => Early warning signs of patient deterioration, unresponsive to verbal commands or GCS < 8 => Late warning signs of patient deterioration ABGs - PaO2 50–60, PCO2 50–60, PH 7.2–7.3 => Early warning signs of patient deterioration, PaO2 < 50, PCO2 > 60, PH < 7.2,=> Late warning signs of patient - It is recommended to first test for the most likely pathogens for a given patient, knowing the optimal test to use for each pathogen. If these first-line tests are unrevealing, saved CSF can be used for follow-up testing. The diagnostic plan should be in place before obtaining a lumbar puncture (LP) so that all desired first-line tests are sent, and no extraneous tests use precious CSF. Specific recommendations include recording the LP opening pressure, collecting at least 20 cc of CSF, saving 5 to 10 cc for future testing, and testing all CSF samples for glucose (along with paired peripheral glucose), protein, white blood cell (WBC) count with differential and red blood cell count. The importance of collecting a large volume of CSF and asking the clinical laboratory to save a portion of it cannot be underestimated. This facilitates additional workup after the most common causes of infection are ruled out, and prevents the need for a repeat LP and interpretation of results confounded by anti infective and anti-inflammatory treatments. In addition to CSF studies, it is important to gather corroborating evidence for CNS infection from peripheral sites, both broadly (with blood cultures) and in a directed fashion (with serologies). HIV testing is particularly important to consider since the differential diagnosis for CNS infection is broader in immunocompromised patients. Baseline serum should also be stored for future testing since some infections are diagnosed by testing acute and convalescent (4–6 weeks) sera. Above all, close bidirectional communication with the clinical pathologists in the microbiology and chemistry laboratories is paramount to ensure that the optimal diagnostic assays are chosen and that tests are followed up in a timely fashion. The value of CSF chemistry and cell counts lies primarily in their ability to rapidly establish the presence or absence of CNS inflammation. Viral pathogens lead to a predominantly lymphocytic pleocytosis while bacterial etiologies result in a neutrophilic predominance and low glucose is an oversimplification of a dynamic process with significant overlap. Certain patterns can be useful to guide further testing, particularly when first-line testing is uninformative. Examples include the moderately low CSF glucose levels typical of mumps and lymphocytic choriomeningitis virus (LCMV), and the persistent neutrophilic pleocytosis found with West Nile virus (WNV) and cytomegalovirus (CMV). An eosinophilic pleocytosis should raise concern for helminth infections. The thermally dimorphic fungus Coccidioides has also been described to cause mild elevation in CSF eosinophils. Whether pleocytosis is present or not, any patient undergoing an LP due to concern for infection should have a CSF Gram stain and culture performed. The sensitivity of Gram staining depends on the organism burden, ranging from 25% for Listeria monocytogenes to upwards of 90% for Streptococcus pneumoniae . Sensitivity drops by 50% if patients have already received antibiotics. A positive Gram stain is highly specific for bacterial meningitis. The specificity of bacterial culture is also high, nearly 100%, but varies by pathogen and decreases with increasing interval between antibiotic exposure and LP. Neisseria meningitidis is sterilized within 2 hours after treatment, while S. pneumoniae can be detected up to 8 hours after initiation of treatment, albeit with low sensitivity. The sensitivity of culture for tuberculous meningitis is estimated to be 60% but can increase to >85% by performing up to four large-volume (10–15 mL) LPs. The primary drawback is that results are not provided in a clinically actionable timeframe due to the slow growth rate of mycobacteria. 71 Based on the description of Amanda’s state we could say that her condition is neurological and infectious. I would perform following tests, which are further described below: LP, CSF (cell count, leukocyte differential, biochemistry, parameters), Serology, Antigen testing, Culture, Gram stain and Microscopy (CSF), PCR, Brain imaging (CT), Blood tests, and Whole genome sequencing techniques. Some of the tests I would consider performing are: Culture - Cerebrospinal fluid (CSF) culture is the gold standard for central nervous system (CNS) infections and can guide antimicrobial therapy. Bacterial cultures are critical in the management of meningitis with varying sensitivities depending on the causative organism. These range from 97% for Haemophilus influenzae, 87% for Streptococcus pneumoniae, and 80% for Neisseria meningitidis. The timing of antibiotics with the acquisition of CSF is crucial. A positive result decreases from 85% before antibiotics, to 73% when obtained less than 4 hours after therapy, 11% between 4 to 8 hours and 0% after 8 hours. Listeria monocytogenes causes both meningitis and rhombencephalitis with associated abscess formation. Cultures are hampered by slow growth and are insensitive due to a low CSF bacterial load. Sensitivities vary between studies and range from 55% to 90% and are as low as 41% in patients with rhombencephalitis. Blood culture performs marginally better in cases of rhombencephalitis with rates reaching 61%. In general, larger CSF volumes improve the sensitivity of culture. However, even with large volumes of CSF, visualization of acid fast bacilli (AFB) by microscopy is only 15% sensitive, and Mycobacterium tuberculosis (TB) can take 2 to 4 weeks to culture with a sensitivity of only 50% to 60%. Therefore, AFB culture cannot be relied on for time-critical TB meningitis diagnoses. Viral cultures are performed with cell lines. The patient sample is added to the culture medium, and cytopathic changes are observed in positive cases. These changes can take up to 30 days to appear depending on the virus. Shell vial culturing, antigen detection, and immunofluorescent antibodies to specific viruses have improved this previously slow turnaround. Enteroviruses are the easiest viruses to culture with 75% sensitivity and a 3- to 8-day test turnaround. Other viruses fail to display equivalent results. Herpes simplex virus (HSV) is only cultured from CSF in less than 5% of HSV encephalitis cases. Fortunately, with the advent of advanced molecular techniques, the need for viral cultures as a diagnostic tool for CNS infections has diminished. Fungal cultures can be performed on specific fungal mediums. However, the 3 most frequent neuroinvasive fungi: Cryptococcus spp, Candida spp, and Aspergillus spp, can be cultured on standard bacterial mediums with variable sensitivity. When more rare fungi are being considered, as may be the case with chronic meningitis, specific culture mediums are required. Serology (Syphilis) – Caused by bacteria Treponema Pallidum, antibody testing is the standard tool for diagnosis and is divided into 2 groups, treponemal and nontreponemal testing. Treponemal tests include fluorescent treponemal antibody absorption (FTA-ABS), T. pallidum particle agglutination (TP-PA), and enzyme immunoassay (EIA). These tests detect antibodies to specific antigenic components of the bacterium. The latter two tests are more sensitive and specific than the older FTA-ABS test. These are opposed to nontreponemal tests, which detect antibodies to lipoidal material released from damaged host cells and cardiolipin-like material released by T. pallidum. The 2 most common nontreponemal tests are the Venereal Disease Research Laboratory (VDRL) slide test and the Rapid Plasma Reagin card test, in which reactive sera produce flocculation of the antigenic material. Treponemal tests remain positive for life after primary infection and are not used as a marker for treatment response. Nontreponemal tests are quantitative and are used to assess treatment response with the expectation that they will either revert to being negative or at least exhibit a 4-fold reduction in titer after successful treatment. However, the nontreponemal tests can be falsely negative either as a result of waning antibody titers in late latent syphilis, or conversely, as a result of very high antibody titers that interfere with the formation of the antigen-antibody lattice, called the prozone phenomenon. If the latter case is suspected in a high-risk patient, the treating physician may ask the laboratory to dilute the biological sample and repeat the test. Because both treponemal and nontreponemal tests are susceptible to false positives and negatives, combined testing is recommended for an accurate diagnosis of syphilis (the syphilis testing algorithm for syphilis screening). A definitive diagnosis of neurosyphilis is based on a clinical syndrome suggestive of neurosyphilis, a positive serum TP-PA, and a positive CSF VDRL. However, CSF VDRL only has a sensitivity of roughly 70% and therefore cannot exclude neurosyphilis. False positives can occur with traumatic taps resulting in contamination from peripheral blood. In the absence of a positive CSF VDRL, a probable diagnosis of neurosyphilis is made with a CSF white blood cell count >5 mm/μL or a protein greater than 45 mg/dL. Treponemal tests are not routinely performed on the CSF despite some suggestions that the high sensitivity of the test should rule out syphilis. Serology (Varicella Zoster Virus) - is a neurotropic virus that can cause a wide range of syndromes from encephalomyelitis, multifocal polyradiculitis, and cranial neuritis to a vasculopathy affecting both small and large cerebral arteries leading to unifocal and multifocal strokes. Symptoms can present after a prolonged duration, and a rash can occur months before presentation and may not be present at all. VZV serum immunoglobulin M (IgM) appears within 2 to 5 days of symptom onset. Levels begin to decrease by 3.5 weeks and cannot be detected by 1 year. IgG levels decrease with time but generally remain positive for life. Therefore, a positive serum IgM is usually indicative of active infection. CSF evaluation displays a pleocytosis in two-thirds of patients, and the diagnosis is made with CSF VZV serology or PCR. VZV IgG levels have higher sensitivity in comparison to PCR, 93% versus 30%, respectively. As most adults will have positive VZV IgG in serum, it is important to assess for a low-serum/CSF ratio to confirm intrathecal production. CSF VZV IgM is also supportive of a diagnosis, despite its less robust sensitivity compared with IgG. VZV PCR may also be dependent on the time of symptom onset and the time of CSF acquisition with decreasing sensitivity of PCR after 1 week. Time-dependent sensitivity is an important consideration given the protracted course and delayed presentation of most cases. Serology (Flaviviruses) – They cause mosquito and tick-borne infections that are endemic to certain regions throughout the world. They can cause meningitis, meningoencephalitis, and anterior horn cell disease. Viremia is detected as early as 1 to 2 days after the primary mosquito bite and persists for up to 1 week until the development of IgM neutralizing antibodies. Viremia is generally absent by the time neurologic symptoms appear in immunocompetent hosts, whereas immunocompromised patients demonstrate a prolonged viremia with a delay in antibody production. The pathophysiology of WNV mirrors the yield of laboratory diagnostics. CSF PCR may be helpful very early in the disease but generally has a low sensitivity (57%). IgM capture enzyme-linked immunosorbent assay (ELISA) in either blood or CSF during the acute phase is the gold standard for the diagnosis of neuroinvasive WNV and is generally always present by the time neurologic symptoms manifest. The large IgM pentameter does not cross the blood-brain barrier, and therefore, its presence in CSF is suggestive of intrathecal production. IgM may be falsely negative in the early phase in immunocompromised patients who have not yet mounted an antibody response, and PCR or repeat CSF IgM assay 7 to 10 days into the illness may be more appropriate in this setting. Despite the high sensitivity of ELISA, the assay has poor specificity because of cross reactivity with other neuroinvasive flaviviruses ( Zika virus, yellow fever virus, St. Louis encephalitis virus, and dengue virus, etc.). Confirmatory testing can be performed using plaque reduction neutralization testing (PRNT) for WNV and other flaviviruses. It is also notable that WNV IgM titers can remain positive for up to 1 year in serum and 7 months in CSF. Therefore, demonstration of a 4-fold or greater increase in virus-specific antibody titer or elevated virus-specific IgG antibodies in the acute or convalescent serum sample confirms acute infection. When Zika virus spread rapidly it led to an increased incidence of microcephaly, Guillain-Barré syndrome, encephalitis, and myelitis. Once Zika virus was recognized as the etiologic, pathogen-specific reverse transcription-PCR and Zika virus IgM serology were used on CSF to detect neuroinvasive disease. Zika virus serology suffered from the same drawbacks as most flavivirus serologies with false positives due to cross-reactivity. However, the Euroimmun anti–Zika fever IgG and IgM ELISA tests demonstrated high specificity for the Zika virus. The Centers for Disease Control and Prevention no longer recommends the PRNT in regions with high prevalence of multiple flaviviruses due to its low accuracy in this setting. Instead, patients are tested for dengue virus and Zika virus on CSF to rule out cross-reactivity. Serology (Lyme Disease) - a tick-borne illness secondary to the Borrelia burgdorferi sensu lato. Lyme disease can present with a wide range of neurologic syndromes, including polyradiculitis, multiple cranial neuropathies, myelitis, meningitis, brainstem encephalitis, and optic neuritis. It is important to conduct tests in patients with an appropriate history and examination for neuroborreliosis, therefore increasing the pretest probability and yield from laboratory investigations. Direct identification of the spirochete is difficult with resultant low sensitivities for cultures and PCR. A diagnosis is achieved through a 2-tier system with EIA followed by Western blot. EIA is highly sensitive, and if positive or equivocal, the Western blot is performed. If the symptoms have been present for less than 1 month, then IgM and IgG are assayed. Two reactive bands constitute a positive IgM, and 5 or more out of 10 possible bands are positive for IgG. If symptoms have occurred for longer than 1 month, then only IgG is performed, although like WNV, IgM antibodies to B burgdorferi can persist for months. IgM alone cannot be used to confirm a diagnosis, and evidence of seroconversion may be required. The current EIA was developed from whole cell sonicates of cultured B burgdorferi with no specific targeted antigen, which leads to a high degree of cross reactivity. The Western blot has poor sensitivity; there are no bands that are more specific for the organism, and multiple antibodies with similar weights may colocate over the same band. Both these tests perform very poorly with 50% sensitivity in early presentations, and serology may take up to 3 to 6 weeks to become positive. Newer serologic tests target specific antigenic proteins, such as C6, on the “variable major protein–like sequence, expressed,” a cell surface lipoprotein. These new assays have demonstrated excellent sensitivity and specificity and may soon replace the Western blot in the 2-tier algorithm. However, they suffer from similar issues of poor sensitivity in early disease, the inability to differentiate between active and past infection and false negatives in immunocompromised patients. A diagnosis of neuroborreliosis is made with a suggestive history and examination consistent with Lyme disease, positive serum serology, CSF pleocytosis, and evidence of intrathecal antibody production. Most patients will display a CSF pleocytosis and elevated protein, except in cases of polyneuropathies. In early neurologic disease, elevated intrathecal antibody production is evident in only 75% of patients but increases to nearly 100% within several months. The IgG index is elevated in 100% of all late neuroborreliosis cases. The index can remain elevated for several years after treatment and cannot be used as a marker for follow-up or clinical activity. Measurement of C6 on CSF has had variable results and sensitivities. CXCL13 is a B-cell–attracting chemokine that has a high sensitivity even before detectable intrathecal antibodies with decreased levels after treatment. False positives have also been found with CNS lymphoma, TB meningitis, and neurosyphilis. Serology (Neurocysticercosis) - (NCC) is caused by infection with Taenia solium, a pork tapeworm. Diagnosis is made on clinical, exposure history, and radiological characteristics with confirmatory laboratory diagnosis. The lentil lectin glycoprotein enzyme-linked immunoelectrotransfer blot (EITB) is a Western blot assay that is considered the test of choice. This assay uses 6 glycoprotein antigens on a strip to detect antibodies to T solium. Appearance of any of the 6 bands is consistent with a systemic infection by the parasite. In patients with 2 or more noncalcified or enhancing lesions on brain imaging, serum EITB carries a sensitivity of 98% and 100% specificity for NCC. However, the EITB performs poorly on samples from patients with single lesions (28%) and calcified lesions. This may be due to a lack of an antigenic response from dead calcified lesions compared with viable cysts. Serum carries a slightly higher sensitivity than CSF. Compared with the EITB, serum ELISA has poor sensitivity (89%) and specificity (93%) due to cross-reactivity with other helminthic infections. This is less problematic in CSF due to fewer non-NCC antigenic components, allowing for a decreased test threshold and increased sensitivity. ELISA also fares poorly with single or calcified brain lesions. The main drawback of serology is false positives in asymptomatic patients from endemic regions and an inability to differentiate between active and inactive infection. Some studies suggest that 40% of positive results in endemic regions are due to transient antibodies that become undetectable within 1 year. For this reason, caution must be used when assessing patients from endemic regions, and weight should not be solely placed on serologic testing, but the entire clinical and neuroradiological information should be considered. Antigen testing - Involves detection of antigenic proteins specific to a microbial source by immunologic methods, such as latex particle agglutination, coagglutination, and ELISA. Antigen testing (neurocysticercosis) - Monoclonal antibody-based antigen testing using ELISA is commonly used for NCC. Antigen levels are higher in patients with viable parasites, extraparenchymal disease, as well as the quantity and size of lesions. CSF samples have a higher sensitivity than serum. Sensitivity is again lower with calcified and single lesions. Antigen testing is used to monitor treatment response because NCC antigen titers should normalize in successfully treated patients. Antigen testing (fungal antigen testing) - A rapid and accurate test for the diagnosis of Cryptococcus neoformans. Testing is done through latex particle agglutination or enzyme immunoassay. The test targets the cryptococcal polysaccharide capsule glucuronoxylomannan. The sensitivity of antigen testing is very high with 99% sensitivity and 97% specificity. The introduction of the point of care lateral flow assay has allowed rapid and accurate diagnosis of Cryptococcus in resource limited settings. The lateral flow assay can be performed on serum, plasma, and CSF. It takes approximately 15 minutes for a result and has a higher sensitivity than standard latex particle agglutination. Antigen titers decrease rapidly in response to treatment but may not normalize, with persisting low titers despite negative cultures, CSF normalization, and clinical improvement. Antigen testing should not be used to assess for cure. Galactomannan, cell wall polysaccharide, is released by Aspergillus species during growth. Galactomannan antigen testing uses antibodies directed against b(1r5)-linked galactofuranosyl residues found on the side chains of galactomannan. Its use for the detection of invasive aspergillosis in immunocompromised patients has been extensively studied in serum and recently in CSF with a sensitivity of 88% in the latter. Specificity is 96% due to cross-reactivity with Trichocomaceae family, Fusarium spp, and Histoplasma capsulatum. Serum false positives can occur from antibiotic therapy (piperacillin tazobactam), bacterial infections, blood transfusions, and dialysis. The sensitivity of the assay increases in patients with hematologic malignancy and severe neutropenia in comparison to solid organ transplant patients and those with mild immunosuppression. 1,3-beta-d-Glucan (BDG) is the major cell wall component of most fungal species, and BDG antigen testing is used as a broad test for detection of fungal pathogens. Cryptococcus spp do not contain high levels of BDG in their cell walls and therefore are not detected. BDG antigen testing helps detect invasive aspergillosis and candidiasis. Most studies were conducted on serum that displayed 60% to 100% sensitivity with a recommended test cutoff of 60 to 80 pg/mL. After a recent outbreak of fungal meningitis secondary to contaminated intrathecal methylprednisolone, studies have suggested that CSF BDG at a cutoff of 138 pg/mL has a 100% sensitivity and 98% specificity for Aspergillus fumigatus, Exserohilum rostratum, Cladosporium cladosporioides, Epicoccum nigrum, and with decreasing titers suggestive of an effective treatment response. PCR (Herpes Simplex Viruses) - Its ability to detect common viral and bacterial pathogens has made it the gold standard in clinical diagnostics. DNA is extracted from a biological sample and heated to separate the nucleic acid. Oligomeric primers for the organism-specific sequences are added with DNA polymerase, leading to transcription of new DNA, which is complementary to the target sequence. This process is repeated multiple times with each new strand undergoing the same process, leading to exponential amplification and increasing sensitivity. Labeled nucleotides are added during the final run to confirm the suspected genomic sequence. The diagnosis of herpes simplex encephalitis (HSE) was revolutionized by the development of a CSF PCR assay. Before this, diagnosing HSE required a brain biopsy because viral culture had only 5% sensitivity. HSV-1, 2 PCR has a sensitivity of 98% and 94% specificity. False negatives may occur within the first 72 hours or after 7 to 10 days of antiviral treatment. If high clinical suspicion exists for HSE, then repeat lumbar puncture (LP) and PCR are required despite an early negative CSF HSV-1, 2 PCR. PCR is available for numerous pathogens, including standard bacterial meningitis pathogens, VZV, enterovirus, human herpesvirus-6, Epstein-Barr virus, cytomegalovirus, JC virus, and WNV. Each PCR has different test performance characteristics, so both negative and positive results have to be interpreted in a clinical context. PCR (Mycobacterium tuberculosis) - The Xpert MTB/RIF is a rapid PCR used as the standard molecular test for the diagnosis of pulmonary TB. Xpert sensitivity for TB meningitis is approximately 50% depending on CSF volume and processing technique. The Xpert MTB/RIF also allows the detection of rifampicin resistance, a key drug in TB antimicrobial regimens. The new Xpert MTB/RIF Ultra is the next generation of the Xpert MTB/RIF and has recently been adopted by the World Health Organization as the test of choice for the diagnosis of TB meningitis. Preliminary studies found a sensitivity of ~95% for TB meningitis when compared with Xpert MTB/RIF or TB cultures combined. However, when tested against the current uniform case definition for TB meningitis, Xpert MTB/RIF Ultra demonstrated a sensitivity of only 70%. Multiplex PCR - a technique in which multiple primers are used allowing detection of several organisms by a single assay. The FilmArray meningitis and encephalitis panel is a rapid, multiplex PCR panel that tests for 14 common viral, bacterial, and yeast pathogens. A recent prospective multicenter trial evaluating the FilmArray displayed a range in sensitivity of 85% to 100% depending on the organism. However, there was also a high rate of false positives and several false negatives. Conventional agent-specific confirmation testing by PCR may be more appropriate in some circumstances. Bacterial and Fungal PCR - The 16s recombinant ribosomal RNA (rRNA) gene is a highly conserved genetic region that is found in all bacteria. The sequence is approximately 1550 base pairs long and contains both hypervariable and conserved regions. Universal primers are used to complement either end of the conserved region. The hypervariable regions contain specific signature sequences useful for bacterial identification at a species level. Fungal pathogens can be identified using a similar process with universal fungal primers targeting the ITS1 and ITS4 conserved regions on the 18s and 28s rRNA sequences, respectively. The amplified sequences include the variable ITS2 region for species identification. In culture proven cases of meningitis, 16s rRNA PCR demonstrated a sensitivity of 94%, a specificity of 94% confirming a bacterial cause, and was positive in 30% of culture-negative cases. In cases of suspected CNS infection with a CSF pleocytosis greater than 500 cells/μL (to increase the likelihood of bacterial pathogens), universal primers to 16s and 18s had a 65% sensitivity compared with 35% by microscopy and culture. The main reason for discordance was pretreatment with antibiotics before LP leading to diminished culture results. 70 Lumbar puncture - Key when it comes to enabling fast confirmation of meningitis and revealing the etiology 68 (the type of infecting organism 69). In the UK, the median time from admission to LP is 17 hours despite national recommendations for an LP to be performed within 1 hour of arrival to the hospital and preferably before antibiotics. The likelihood of detecting a pathogen decreases over time and, while getting an LP done within an hour is not always possible, it should be done as soon as is practically possible. In patients with predominantly sepsis or a rapidly evolving rash, LP is not recommended. 68 The diagnostic yield of LP can be diminished by collecting small CSF volumes. At least 10 mL can be safely removed. 69 CSF cell count - The cerebrospinal fluid remains one of the most rapidly informative tests. Pleocytosis indicates meningeal inflammation, of which infection is the most common cause.69 Over 90% of adults with bacterial meningitis have a CSF leukocyte count >100 cells/μL. The absence of leukocytosis makes meningitis unlikely but does not rule it out. An absence of leukocytosis was found in 2% of patients with bacterial meningitis, with a higher frequency in pneumococcal meningitis. 68 Approximately 1–2% of patients with bacterial meningitis will have a normal CSF leukocyte count. Positive pathogen detection and an absence of pleocytosis more frequently occur among children, the immunocompromised, those pretreated with antibiotics, or with mycobacteria tuberculosis infection. 69 CSF leukocyte differential - Cerebrospinal fluid leukocyte differential can help predict which type of pathogen is causing infection. 69 The predominance of lymphocytes suggests viral meningitis. Important exceptions include a predominance of lymphocytes in bacterial meningitis if antibiotics have been given before LP and with certain bacteria (such as Listeria monocytogenes and in tuberculous meningitis). A predominance of neutrophils can be seen in early viral meningitis as well, especially with enterovirus. 68 CSF biochemistry - Cerebrospinal fluid glucose is normally approximately two-thirds the blood (plasma) concentration. It is often lower in bacterial and tuberculous meningitis. As CSF glucose is influenced by the plasma glucose, it is essential to measure blood glucose at LP, to obtain an accurate CSF: blood glucose ratio. A CSF: blood glucose ratio 10 mL of CSF and subsequent cytospin. Cerebrospinal fluid culture is historically regarded as the ‘gold standard’ for the diagnosis of bacterial meningitis. 69 CSF culture is diagnostic in 70% 85% of cases before antibiotic exposure. However, in a recent UK study, CSF culture was positive in only 23% of cases of bacterial meningitis when the median time to LP was several hours after antibiotic administration. 68 Sensitivity decreases by 20% following antibiotic pretreatment. Lumbar puncture should be performed as soon as possible to maximise pathogen detection. 69 CSF sterilization can occur within 2 hours and 4 hours of antibiotic administration for meningococci and pneumococci, respectively. 68 CSF polymerase chain reaction (PCR) - Using pathogen-specific nucleic acid sequences, can detect both bacteria and viruses quickly with high sensitivity/specificity in the CSF. It has far greater sensitivity than culture in invasive meningococcal disease. 69 It is the gold standard for the detection of viruses and is increasingly relied upon in the diagnosis of bacterial meningitis, especially when antibiotics have been given before LP. Over 50% of meningococcal disease is diagnosed by PCR alone in the UK. Multiplex PCR, which can detect multiple pathogens at once, is increasingly being used with reasonable diagnostic accuracy reported. 68 PCR for 16S ribosomal RNA (present in almost all bacteria) enables a broad screen for bacteria but has lower sensitivity than pathogen-specific PCR. 69 Whole genome sequencing techniques - Different sequencing methods on CSF identified unexpected pathogens not detected by conventional methods. However, they failed to detect some pathogens found by conventional microbiological testing. Further work is needed to evaluate the clinical impact of such techniques. 68 Blood tests - Blood cultures should be taken in all cases of suspected meningitis 68 on admission, they are helpful when antibiotics are started before LP. Blood cultures are positive in 50–80% of bacterial meningitis cases. Blood meningococcal and pneumococcal PCR are also recommended and have been shown to substantially increase detection of meningococcal disease, and remain positive for several days after antibiotic initiation. Blood PCR is increasingly important, especially as PCR detects bacteria several days after antibiotic initiation. Blood PCR substantially increases the confirmation in meningococcal disease. 69 Although some studies have shown procalcitonin has good sensitivity and specificity for differentiating bacterial from viral meningitis, it should be interpreted with the rest of the clinical picture not be the sole determinant. 68 Despite these tests, many patients will not have a cause when it comes to meningitis. Blood biomarkers, such as procalcitonin and C-reactive protein, can help distinguish bacterial from viral meningitis in adults and can be used to help guide treatment if no etiology is found. 69 Swabs - Throat, nasopharyngeal, and stool swabs are useful for detecting enteroviruses if the CSF PCR is negative. Methicillin-resistant Staphylococcus aureus screening swabs should be taken. A bacterial throat swab should also be taken from cases with suspected meningococcal disease to provide information about the infecting strain in PCR-confirmed cases. 68 Brain imaging - Brain imaging is neither obligatory in the management of meningitis nor a prerequisite to LP. 69 In the majority of cases of suspected meningitis brain imaging is not required and LP can be performed without. Despite this, a UK study showed that 94% of patients had brain imaging before LP and an earlier study showed brain imaging resulted in delays in LP of 10 hours. Furthermore, brain imaging before LP results in delays in antibiotic initiation, which leads to increased mortality. An urgent computed tomography should be performed if there are clinical signs of a brain shift that may indicate a contraindication to LP.68 Clinical features indicative of a brain shift include focal neurological signs and reduced Glasgow Coma Score (GCS). 69 When brain shift is identified, liaison with critical care and neurosurgical teams is essential. Imaging should also be considered if there has been a deterioration following an initial improvement to look for complications, such as subdural empyema. 68 Meningitis guidelines recommend an LP be performed without prior neuroimaging if the GCS is >12. Patients with a GCS ≤12 should be considered for critical care, intubation assessment, and neuroimaging. Imaging, particularly when contrast is used, may exhibit meningeal enhancement in meningitis. 69 - This is a serious form of meningitis. Even with proper diagnosis and treatment, up to 1 in 5 people who develop this condition will die. Long-term health problems occur in around 20% of people who survive pneumococcal meningitis. These problems include brain damage, deafness, learning disabilities, paralysis: Because this disease is so dangerous, it’s very important to go to the doctor right away if you suspect you have it. 98 Although, pneumococcal meningitis is a very serious form of meningitis, I think Amanda’s prognosis is good, because she has not had a very severe form of pneumococcal meningitis.

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R1_CS1_O1_2023/2024

Prompt treatment at a comprehensive stroke center can maximize a patient’s chances of achieving the best possible outcome. Treatment varies by case. The selection of and timing for each procedure depends on a great variety of factors and is discussed to determine the best treatment for each patient.16 Treatment options for SAH include: Computer Assisted Surgery (CAS) - (image-guided surgery) Is an operation in which imaging scans and computer technology are used to make a 3D model of an organ (in the case of neurosurgery, the brain).17 Craniotomy - the temporary removal of a small portion of the skull bone (may be performed to obtain access to the brain to treat any one of several conditions).18 Embolization Endovascular Aneurysm Treatment - This is a method of blocking or repairing cerebral aneurysms. Doctors perform this surgery from inside a patient’s blood vessels.19 Endovascular Neurosurgery – (known as interventional neuroradiology -INR, endovascular surgical neuroradiology -ESNR) is brain surgery performed from inside blood vessels. Doctors thread catheters through blood vessels, pass tiny instruments through the catheters, and use those instruments to conduct the procedures. 20 Gamma Knife Radiosurgery – A very precise form of radiation therapy that focuses intense beams of gamma rays with pinpoint accuracy to treat lesions in the brain. 21 Microsurgery - An array of procedures for which surgeons use a high-powered operating microscope and specialized instruments to operate on small or delicate structures in the brain.22 Stenting - The process of implanting a tube called a stent inside an artery. They are used as part of a procedure to create a safe alternative path for blood flow, away from an aneurysm at risk of rupture. The first step in this procedure is to treat the aneurysm with coil embolization. Then a stent prevents fresh blood from entering the aneurysm, helping it heal, and also prevents the materials used in embolization from blocking blood flow in the normal arteries.23 Aneurysm Clipping In general, surgical treatment options for an aneurysm include clipping, coiling, flow diversion, embolization, or resection. Surgical treatment options for AVM include embolization, resection, or radiosurgery. Clipping - Using an open surgical procedure to place a clip that squeezes the aneurysm’s blood supply closed with an open surgical procedure. Coiling - Using a minimally invasive radiology procedure to fill the aneurysm with tiny metal coils that cause blood to clot. Flow diversion - Inserting a tube in an artery that directs blood flow past the aneurysm. Embolization - Injecting a glue-like substance into the lesion that encourages blood there to clot. Resection - Removing the aneurysm or AVM. Radiosurgery - Delivering precise beams of radiation that slowly shut down the affected vessels. 16 Doctors must also manage possible complications of subarachnoid hemorrhage, such as vasospasm. They often occur 7-9 days after the initial bleed, though they can occur as long as three weeks later. Since vasospasm is a leading cause of poor outcomes, patients generally stay in the hospital for up to three weeks after the initial subarachnoid hemorrhage so they can be monitored for vasospasm. Vasospasms may often be treated with medication. If it is resistant to medication, vasospasm can be treated with endovascular techniques. The patient remains in a dedicated Neuro ICU during the at-risk period. Doctors also monitor patients for hydrocephalus, problems with the lungs or heart, and other conditions that can arise after subarachnoid hemorrhage. 16 The goals of treatment are to save a life, repair the cause of the bleeding (hemorrhaging), relieve symptoms, and prevent complications, such as vasospasm, hydrocephalus, and permanent brain damage. 24 Life-saving treatment and treatment to manage symptoms can include life support (it replaces or supports a failing organ 25), placing a draining tube in the brain to relieve pressure, methods to protect the airway, medication to decrease swelling in the skull, medication given through an IV to manage the blood pressure, medication to prevent artery spasms (vasospasms), painkillers and anti-anxiety medication to relieve headaches 24 (commonly used pain-relieving medicines include morphine and a combination of codeine and paracetamol 26), medication to prevent or treat seizures (anticonvulsants, such as phenytoin – which can help prevent seizures – fits 26), antiemetics (such as promethazine, which can help to stop feeling sick and vomiting26).To treat the subarachnoid hemorrhage and its cause, you may need surgery to remove large collections of blood or relieve pressure on your brain if the SAH is due to an injury, and repair the aneurysm if the SAH is due to an aneurysm rupture. 24 Nimodipine is a medication usually used if one of the main complications of a subarachnoid hemorrhage secondary cerebral ischaemia occurs. This is where the supply of blood to the brain becomes dangerously reduced, disrupting the normal functions of the brain, and causing brain damage. It is normally taken for 3 weeks until the risk of secondary cerebral ischaemia has passed. 26

- Spontaneous intracranial hemorrhage can be parenchymal, intraventricular, subarachnoid, subdural, and epidural, the former one being the most common location and the latter two being uncommon, usually associated with trauma. The most common etiologies of nontraumatic intracranial hemorrhage based on age and anatomical location are: Parenchymal Elderly: Hypertensive hemorrhage, Cerebral amyloid angiopathy (CAA), Hemorrhagic transformation of acute ischemic infarction, Dural AVF, Venous thrombosis, Coagulopathies, Neoplasms Middle-aged and young: Brain AVM, Cavernomas, Venous thrombosis, Hypertensive encephalopathies/PRES, RVCS, Drug abuse, Neoplasms Adolescent, child, and infant: Brain AVM, Cavernomas, Venous thrombosis, Tumors, Coagulopathies (congenital/acquired) Newborn: Hypoxic-ischemic injury Subarachnoid Elderly: Aneurysm, Cerebral amyloid angiopathy (CAA), Perimesencephalic hemorrhage, Bleeding diathesis (e.g., excessive anticoagulation) Middle-aged and young: Aneurysm, Arterial dissection, Brain AVM Adolescent, child, infant, and newborn: Aneurysm, Sickle cell disease (in children), Coagulopathies (congenital/acquired) Epidural/subdural Elderly, young, and middle-aged: Dural AVF, Aneurysm, Moyamoya syndrome, Dural metastases, Bleeding diathesis/hematological disorders 73 There are multiple potential causes of hemorrhage, that can be mainly categorized by the hemorrhage location and the age of a patient, making easier the imaging differential diagnosis approach. Additional imaging to evaluate an intracranial hemorrhage consists of CT angiography to look for underlying vascular lesions and MRI to rule out other etiologies. Vascular imaging is indicated when a vascular lesion is suspected (arterial aneurysms, pial arteriovenous malformations, dural arteriovenous fistula, vasculitis). CT or MR venograms help depict the presence of cerebral venous thrombosis, especially dural sinus thrombosis. CTA and MRA are the initial imaging methods, while DSA is reserved for inconclusive cases and the treatment of some of the vascular lesions. The spot sign on CTA, reflecting contrast extravasation, depicted as an enhancing focus within the acute hematoma is associated with a higher risk of growth of the hematoma. Among the adult population, brain hemorrhage is mainly associated with systemic hypertension, and cerebral amyloid angiopathy, known as CAA. In younger patients and children the most important cause of brain hemorrhage is vascular malformations, and cerebral venous thrombosis (mostly in females during pregnancy and puerperium). Hemorrhagic transformation of acute ischemic stroke and hemorrhagic brain tumors are other important causes of brain hemorrhage. Potential causes of brain hemorrhage, which represent less than 10% of cases are for example reversible cerebral vasoconstriction syndrome - RVCS, posterior reversible encephalopathy syndrome - PRES, vasculitis, coagulopathy disorders, drug consumption, moyamoya disease, infections, pre-eclampsia/eclampsia. Hypertensive hemorrhage is the leading cause of cerebral hematomas in the adult population, being secondary to a long-standing hypertensive vasculopathy characterized by lipohyalinosis of small-to-medium penetrating arteries. Hematomas result from the rupture of small arterioles and have a rebleeding rate of up to 2% per year. Typical locations for hypertensive hemorrhage include basal ganglia (in 62–65% of cases), thalamus (in 20–26% of cases), pons (in 5–10% of cases), cerebellum (in approximately 6% of cases), and subcortical-cerebral lobar (in 1–2%) of cases. The association of leucoaraiosis, lacunar infarcts, and microbleeds with a central distribution pattern supports the diagnosis. Cerebral amyloid angiopathy (CAA) is the second most common cause of spontaneous intracranial hemorrhage in adults and results from the vessel wall deposition of amyloid-b peptide in small leptomeningeal and cortical vessels. CAA is responsible for up to 50% of spontaneous hemorrhages in older patients (>65 years) and its incidence increases with patient age, being present in up to one third of brain autopsies in patients above 60 years old, which reflects that in an ageing population it will be a very important cause of hemorrhage. The most common type of CAA is the sporadic type occurring in the elderly, but there are hereditary types that may present earlier, such as the HCHWA-Dutch type and HCHWA Icelandic type with onset in the third/forth decade, and other reported familiar types. Imaging is an important criterion for the diagnosis of CAA. CAA should be considered in cases of older patients with multiple lobar, cortical, and/or subcortical hemorrhages; superficial/cortical subarachnoid hemorrhage (superficial siderosis); and peripheral distributed microhemorrhages. Hemorrhages rarely involve the cerebellum and the microbleeds spare the basal ganglia and brain stem. For brain hematomas, some red-flag imaging findings should prompt special attention. These cases may require early surgical treatment. It is essential to depict early hematoma expansion, intracranial hypertension, and/or signs of mass effect, such as brain herniation, and the presence of hydrocephalus. Predictors for the worst outcome include hemorrhage volume, infratentorial location (brain stem and/or cerebellum), presence of intraventricular hemorrhage, and/or hydrocephalus. Hematoma volume can be measured from multiplanar reconstruction as the ratio ABC/2, being ABC the three orthogonal diameters (the diameters are multiplied—length × width × height—and divided by 2). It is also essential to depict intraventricular extension, since it represents a higher risk for hydrocephalus, especially if the clot is inside the aqueduct and/or IV ventricle. Brain herniation is associated with a dismal outcome, and may necessitate surgical decompression. Other unfavorable factors of brain hematomas include advanced age, and high scores on the Glasgow Coma Score (GCS) and National Institutes of Health Stroke Scale (NHIHSS) at admission. The ICH score allows an early estimation of the patient's prognosis. Higher scores are associated with higher 30 days mortality rates, namely 13%, 26%, 72%, and 97% corresponding to scores of 1, 2, 3, and 4, respectively. Another brain hemorrhage prognostic score, that estimates functional independence at 90 days, is the Functional Outcome in Primary Intracerebral Hemorrhage (FUNC) score. 30% of brain hematomas will increase in size during the first 24 h, especially during the first 3 hours after presentation, which may be associated with neurological decline. It is important to repeat CT scans at 24 hor whenever there is a neurological decline. Intracranial venous thrombosis (IVT) is an important cause of intracranial hemorrhage, especially in young patients and children. There is also a higher incidence during pregnancy and puerperium and in females under oral contraception. IVT results from the formation and propagation of a venous clot leading to the occlusion of the intracranial venous system components. Venous thrombosis features a wide spectrum of clinical and imaging presentations. Headache is the most common symptom. The diagnosis of IVT includes the demonstration of the thrombus/venous occlusion, depicted by CT or by MRI by the loss of the normal venous flow void by a clot that follows the same signal intensity progression previously described for parenchymal hematomas. MRV or CTV is also helpful to establish the diagnosis. It is also important to depict the presence of intracranial lesions (indirect signs), such as brain swelling, brain edema, venous infarction, intracranial hemorrhage, which are better defined by MRI. Vascular malformations are the leading cause of spontaneous intracranial hemorrhage in children and young patients, including cavernomas and brain arteriovenous malformations (AVMs). Brain AVMs are composed by abnormal arteriovenous shunts, occurring in a central nidus, which is the central area towards multiple feeding arteries converge and from which (early and enlarged) draining veins start. Most of the cases are sporadic, but they may be associated with HHT/ROW and RASA 1 mutation or being a part of metameric syndromes. Brain AVMs appear as a tangled cluster of abnormal vessels, dilated arteries and veins, which can be sulcal, parenchymal, and/or intraventricular. Brain AVMs are constituted by feeding arteries, with the nidus corresponding to the shunting area and veins that drain the malformation. The vessels present slightly hyperdense on CT and with flow voids on MRI. Small AVMs may only be depicted by DSA which is the gold standard imaging method. They can be associated with surrounding brain changes such as edema, gliosis, previous hemorrhage, and/or mass effect. The most common brain AVM classification used is the Martin-Spetzler classification which evaluates the size, location, and venous drainage of the brain AVM predicting the surgical risk for treatment. The hemorrhagic risk is higher for those AVM that have previously bled and those with infratentorial, deep location, and deep venous drainage. Cavernomas are venous vascular malformations that are seen on CT as isodense or hyperdense lesions with calcifications in up to 40–60% of cases. On MRI their appearance is variable. Most commonly they have a central core with the mixed signal from blood in different stages, being hyperintense on T1WI and hyper-hypointense on T2 WI. There is generally a completely T2 hypointense rim of hemosiderin and the contrast-enhancement is variable. The T2∗/susceptibility sequences are the most sensitive imaging methods to depict cavernomas. Cavernomas may appear only as small punctate lesions that are poorly or not seen on T1 and T2 and only demonstrated on T2∗/susceptibility sequences. DSA is negative for the detection of cavernomas. Most of the cavernomas are sporadic but there are some forms, such as CCM 1–3, for which cases multiple cavernomas are more common and an entire evaluation of the neuraxis is suggested. The most common presentation of cavernomas and brain AVM are hemorrhage, seizures, and neurological deficits. Dural arteriovenous fistulae (AVF) tend to present in older patients. They are acquired vascular malformations in which there are abnormal connections between arteries that normally feed the meninges, bone, or muscles, but not the brain, and the dural sinuses or small venules within the dura mater. They are difficult to depict since there is no evident nidus and the feeding arteries are not as dilated as in brain AVM. The dilatation of meningeal arteries, presence of small arteries at the dura sinus and/or arterialized dural sinus, diffuse venous congestion, and/or dilated veins should raise the suspicion of dural AVF. The hemorrhage risk of dural AVF is higher when a cortical venous reflux is present. The most common classifications, the Cognard and the Borden classifications address the type of venous drainage and predict the future risk for hemorrhage. Brain tumors are responsible for approximately 10% of intracranial bleedings. Early diagnosis allows for specific treatment. The most common causes of hemorrhage associated with brain tumors are intratumoral and/or extratumoral hemorrhage from the tumoral mass, generally in hypervascularized tumors. Other causes of hemorrhagic stroke may exist in neoplastic patients, such as malignancy-induced coagulopathy, side effects from chemotherapy and/or radiotherapy, hemorrhagic infarcts resulting from thrombotic coagulopathy, arterial tumoral emboli (in association with heart myxoma), or from venous thrombosis in thrombotic coagulopathy or in association with venous compression/invasion/thrombosis. The tumors more commonly associated with brain hemorrhage are metastases, especially from breast and lung (bronchogenic) carcinoma, melanoma, choriocarcinoma, renal cell carcinoma, thyroid carcinoma, and primary highly vascularized tumors, such as high-grade gliomas. Some imaging findings raise the susicion of the presence of an underlying tumor, such as atypical hematoma location, the presence of multiple hemorrhagic foci within the lesion, heterogeneous hematoma with different hemorrhage stages not following the usual chronological evolution or having a delayed evolution (due to hypoxic environment), the presence of fluid-fluid levels, that may represent blood-blood levels, blood-cystic/necrotic levels, the presence of an incomplete hemosiderin rim, the presence of irregular margins, the presence of disproportionately larger edema, and/or the presence of non-hemorrhagic enhancing areas, The presence of non-hemorrhagic enhancing areas may be more conspicuous and there is generally a persisting mass effect and edema that does not subside completely. Congenital or acquired coagulation disorders are important causes of spontaneous brain hemorrhages since the number of patients under anticoagulation/antiplatelet therapy has been increasing. These hemorrhages can occur in any intracranial compartment, even simultaneously. The presence of large or multiple and synchronous (same age/stage bleedings at CT/MRI) hemorrhages, and/or the presence of fluid-fluid hemorrhagic levels should raise the suspicion of coagulation disorder. It is not common to have brain hemorrhages associated with intracranial infections. Some of the typical examples include hemorrhagic encephalitis, such as herpes encephalitis, dengue fever, Crimean hemorrhagic fever-Congo virus, Epstein Barr virus, and chikungunya virus, among others. Hemorrhage may also be a presentation of infectious vasculitis, such as varicella-zoster vasculitis. Fungal infection with vessel wall invasion may cause hemorrhage, e.g. in cases of aspergillosis and mucormycosis. Actinomycosis, paragonimiasis, and cerebral malaria (due to hemorrhagic infarcts) may also present with devastating hemorrhagic lesions. Other causes of hemorrhage include infective endocarditis with septic emboli, hemorrhage associated with sepsis-induced coagulopathy, and infection treatment as in toxoplasmosis. In cases of meningitis, cerebral venous thrombosis and hemorrhagic transformation of ischemic infarcts may also lead to brain hemorrhage. The overall incidence of SAH is between 9 and 20 per 100,000 person-years, accounting for up to 5% of all stroke cases. The most common cause of spontaneous subarachnoid hemorrhage (SAH) is the rupture of an intracranial aneurysm, accounting for up to 80–85% of cases. Ruptured saccular aneurysms commonly present with SAH located in the basal cisterns. Additional causes of SAH include intracranial dissections, and cases with superficial/cortical subarachnoid hemorrhage, CAA, cortical venous thrombosis, vasculitis, reversible vasoconstriction syndrome (RVCS), distal arterial aneurysms, and dural arteriovenous fistulae (dAVF) should be considered. Benign perimesencephalic SAH is a subgroup of SAH with an excellent prognosis. It accounts for up to 10% of cases and is believed to result from rupture of veins. Typically, the blood is collected at the perimesencephalic and prepontine cisterns and CTA and DSA are negative for the presence of aneurysm/vascular malformation. Isolated intraventricular hemorrhage is an uncommon location for spontaneous hemorrhage. It generally results from the direct expansion of a parenchymal hematoma or the recirculation of blood in an SAH case. Epidural and subdural hematomas are generally associated with head trauma. Exceptionally they may occur spontaneously in patients under anticoagulation or antiplatelet therapy. Isolated spontaneous EDH and SDH have been described most commonly in association with coagulopathies, dural and osteodural arteriovenous fistula, intracranial hypotension, and dural/bone tumors, especially metastases. Imaging is essential for the management of intracranial hemorrhage. It allows for the depiction of the bleeding, the classification of the hemorrhage according to its size and location, to detect and/or exclude an underlying disorder, such as a vascular malformation, tumor, infection, among others. It also establishes the prognosis and guides the treatment. Clot formation and imaging - Primary acute intracerebral hemorrhages appear on non contrast-enhanced CT as lesions of homogenous hyperattenuation. The hyperattenuation is a result of the increasing protein density in the hematoma. With the maturing of hematoma, there is progressive clot formation and retraction with fluid loss, which then leads the hyperattenuation to increase from a range of 40–80 HU to 80–100 HU. In the acute phase, the presence of fluid (fluid levels) and or hypoattenuated areas inside the hematoma can represent a hyperacute hematoma, active bleeding with the new incoming blood corresponding to the hypoattenuating areas, and or the presence of coagulation disorder, which can be acquired or congenital. The “swirl sign” characterized by the mixture of different densities or MR signal intensities in an acute hemorrhage suggests active bleeding. Clots usually become isodense to the brain on CT images at 8–14 days after hemorrhage, then progressively hypodense after 2 4 weeks, and at the late subacute and chronic phases, they are typically hypodense approaching the attenuation of cerebrospinal fluid (CSF). Initially, an intracerebral hematoma consists of intact red blood cells, which contain mostly oxygen-saturated hemoglobin - oxyhemoglobin, OxyHb. The hemoglobin gets then gradually deoxygenated. At 48 h after hemorrhage, the clot consists almost entirely of deoxyhemoglobin - DeoxyHb. The hematoma is surrounded by edema at this stage. In the early subacute phase which is from 3 to 7 days, DeoxyHb is gradually converted to methemoglobin - MetHb. The changes begin at the periphery of the clot and later progress towards the center. In the late subacute phase which is from 2 to 4 weeks, the RBCs lyse and MetHb is released from the intracellular into the extracellular space. The edema gradually dissolves in this stage. Later, in the chronic phase which is after more than 4 weeks, the hematoma shrinks to form a small cavity, often slit-like. The cavity frequently contains ferritin- and hemosiderin-laden macrophages as long-standing markers of bleeding. The signal intensity changes occur from the periphery to the center in a homogeneously layered fashion, the evolution over time will depend on the location of the bleeding. Over the following hours and days, it is expected that there will be an increase in the surrounding brain edema and mass effect. The surrounding edema increases during the first 2 weeks (mainly during the first 48–72 h), and it is associated with the activation of inflammatory pathways initiated by the products of hematoma. On post-contrast imaging (CT/MRI), a thin regular ring-like enhancement at the periphery of the hematoma is visible during the subacute phase, as a result of local disruption of the blood-brain barrier and associated inflammatory reaction. The hematoma density will gradually decrease over time, (results from clot lysis and liquefaction), with a centripetal course, from the periphery to the center, at an estimated rate of 0.7–1.5 HU per day. The edema and the mass effect normally tend to start to fade at late subacute phases, normally after the third week. In the late and chronic phases, the edema and mass effect will subside and a slit-like hemosiderin scar will prevail as a hypoattenuation on CT and low T1 and T2 WI signal lesion without edema and mass effect. Chronic lesions are associated with brain atrophy with sulcal and or ventricular enlargement and can exhibit focal calcification and peripheral gliosis. Microhemorrhages are defined as small chronic punctate brain hemorrhages (only depicted by MRI using T2∗W susceptibility imaging). They are depicted as small (less than 5 mm) rounded low T2∗ lesions that result from presumed ruptures of tiny vessels with diameters smaller than 200 μm. They are frequently associated with sporadic small vessel disease (systemic hypertension) and CAA. They may also be found in patients with nonsporadic small vessel diseases, such as CADASIL and vasculitis. They are also seen in aging with increasing prevalence with older age and hypertension. The differential diagnosis of microbleeds includes non-hemorrhagic subcortical mineralization areas; pneumocephalus and hemorrhagic lesions such as cavernomas, hemorrhagic diffuse axonal injury, and microhemorrhagic brain metastasis. The microhemorrhage pattern associated with chronic hypertension has a central distribution, located at the deep gray structures known as basal ganglia and thalamus, cerebellum, and at the cerebral cortico-subcortical junction. The CCA pattern has a peripheral distribution at the cerebral lobar cortico-subcortical areas with a posterior predominance. Subarachnoid and intraventricular hemorrhage manifest with hemorrhage into the CSF spaces presenting with increased attenuation - blood on CT images. The hemorrhage attenuation and MRI signal intensity follow the above-mentioned evolution. The severity of the SAH is measured by the modified Fisher grade. The pattern of blood distribution, namely basal cistern, superficial, or perimesencephalic distribution, allows the prediction of the etiology. 72 - Risk factors for subarachnoid hemorrhage include: An unruptured aneurysm in the brain or elsewhere in the body - Aneurysm is a bulge in the wall of an artery that forms when there’s a weak area in the artery wall. They can burst when being untreated leading to internal bleeding, and also cause blood clots that block the flow of blood in the artery. A rupture or clot can be life-threatening based on the location of the aneurysm. 2 History of a previously ruptured brain aneurysm Cigarette smoking – The use of tobacco harms every organ in the body because smoking tobacco brings nicotine and over 5,000 chemicals, including numerous carcinogens into the lungs, blood, and organs. The damage caused by smoking can shorten the lifespan significantly. 3 High blood pressure (hypertension) – Occurs when the force of blood pushing against the artery walls is consistently too high, this damages the arteries over time and can lead to serious complications like (heart attack, stroke, etc.). 4 Fibromuscular dysplasia (FMD) – A condition that involves abnormal cell growth in the walls of arteries (it can make the blood vessels narrow, bulge, or develop a beaded appearance) 5, Ehlers-Danlos syndrome - a genetic condition that affects the connective tissues in your body (people with EDS have weaker collagen, meaning their connective tissue isn’t as strong or supportive as it should be, it can affect any connecting tissue including cartilage, bones, blood, fat) 6, and other connective tissue conditions. History of polycystic kidney disease - A genetic disorder that causes cysts to grow in the kidneys, where they can disrupt functioning (health complications include high blood pressure and kidney failure - the cysts can enlarge the kidneys and prevent them from filtering waste out of the blood). 7 Cocaine and or methamphetamine use – May increase the risk of medical issues, some can be life-threatening, (such as heart attack, stroke, HIV/AIDs, hepatitis C, pneumonia, increased seizures related to epilepsy), and over time, cocaine use may change other brain functions. ( For example, the amount of glutamate – a neurotransmitter that sends messages between nerve cells in the brain, plays a role in learning and memory, so with long-term cocaine use the thinking processes and the ability to remember information are dulled. Cocaine use can also make the brain’s stress receptors more sensitive to stress - people react more strongly to stressful situations). 8 Excessive alcohol consumption - Can lead to the development of chronic diseases and other serious problems including high blood pressure, heart disease, stroke, liver disease, digestive problems, cancer (breast, mouth, throat, esophagus, voice box, liver, colon, rectum), weakening of the immune system, learning and memory problems ( for example dementia and poor school performance), mental health problems (such as depression and anxiety), social problems (family problems, job-related problems, unemployment,...), alcohol use disorders, or alcohol dependence. 10 Use of blood thinners, such as warfarin - It prevents and treats blood clots. 9 A strong family history of aneurysms When it comes to Mrs.Anna she smokes, which is one of the risk factors. 11

Mrs. Anna is presented with the following symptoms that confirm the doctor's diagnosis: nausea or vomiting, severe headache that is described as the worst headache pain ever and feels different from other headaches, sensitivity to light, and neck stiffness. Other common symptoms of a subarachnoid hemorrhage that Mrs. Ann does not have include loss of consciousness, double vision, trouble speaking, drooping eyelid, confusion and trouble concentrating, and seizures.

- Meninges are three membrane layers that cover and protect the central nervous system – the brain and spinal cord. These membranes are the dura mater, arachnoid mater, and pia mater. 1 The meninges protect the central nervous system from trauma injury to the brain, such as a blow to the head by acting as a shock absorber. They protect and anchor the central nervous system and keep the brain from moving around within the skull. The meninges also provide a support system for blood vessels (including the middle meningeal artery), that deliver blood to the central nervous system tissues, nerves (including the trigeminal and vagus nerves), lymphatics - drainage system, and cerebrospinal fluid that surrounds the central nervous system. 1 Dura mater - The outer layer that is the closest to the skull. Your dura mater is the outer, thick, strong membrane layer located directly under your skull and vertebral column. In Latin, dura mater means “hard mother.” It consists of two layers of connective tissue. One side of your dura attaches to your skull and the other adheres to your middle membrane layer (arachnoid mater). Your dura mater contains a drainage system, called the dural venous sinuses, which allows blood to leave your brain and allows cerebrospinal fluid to re-enter the circulation. Your dura mater receives its blood supply from your middle meningeal artery and vein, and your trigeminal nerve runs through it. 1 Your dura mater folds inward onto itself to form four thin membrane layers called dural reflections. Each dural reflection surrounds different sections (hemispheres) of your brain. Arachnoid mater - The middle layer of the meninges. It is a thin layer that lies directly below the dura mater - between the dura mater and pia mater. It does not contain blood vessels or nerves and it has a spiderweb-like appearance known as “arachnoid” (meaning – spider) because it has connective tissue projections that attach to the pia mater. Between the arachnoid mater and the pia mater is the subarachnoid space, which contains cerebrospinal fluid that helps cushion the brain. 1 Pia mater - The inner layer that is the closest to the brain tissue. The pia mater (the innermost layer) is a thin layer that is held tightly (like shrink wrap) to the surface of the brain and spinal cord. Many blood vessels pass through this layer to supply your brain tissue with blood and the pia mater also helps contain cerebrospinal fluid. In the spinal cord, the pia mater helps maintain the stiffness of the cord. 1 The arachnoid mater and pia mater together are called leptomeninges. The three spaces within the meninges: The epidural space - A space between the skull and dura mater and the dura mater of the spinal cord and the bones of the vertebral column. Analgesics, also known as pain medicine, and anesthesia are sometimes injected into this space along the spine. The spinal cord ends between the first and second lumbar vertebra in the middle of the back, at which point, only cerebrospinal fluid is present. This is the site where a lumbar puncture, also known as a “spinal tap” is performed. 1 The subdural space - A space between the dura mater and the arachnoid mater. Under normal conditions, this space isn’t a space but if there is a trauma to the brain, for example, a brain bleed, or other medical conditions it can be opened. 1 The subarachnoid space - A space between the arachnoid mater and pia mater. It is filled with cerebrospinal fluid, which cushions and protects the brain and spinal cord.1 - The circle of Willis is a junction of several important arteries at the base (bottom part) of the brain. It helps blood flow from both the front and back sections of the brain. The structure encircles the middle area of the brain, including the stalk of the pituitary gland and other important structures. The two carotid arteries supply blood to the brain. They run along either side of the neck and lead directly to the circle of Willis. Each carotid artery branches into an internal and external carotid artery. The internal carotid artery then branches further into the cerebral arteries. This structure allows all of the blood from the two internal carotid arteries to pass through the circle of Willis. The structure of the circle of Willis includes left/right internal carotid arteries, left/right anterior cerebral arteries, left/right posterior cerebral arteries, left/right posterior communicating arteries, basilar artery, and anterior communicating artery. The circle of Willis is critical because it is the meeting point of many important arteries supplying blood to the brain. The internal carotid arteries branch off from here into smaller arteries, which deliver much of the brain’s blood supply. The circle of Willis plays an important role, it allows proper blood flow from the arteries to both, the front and back hemispheres of the brain. The arteries that stem off from the circle of Willis supply much of the blood to the brain. The circle of Willis also serves as a sort of safety mechanism when it comes to blood flow. If a blockage or narrowing slows/prevents the blood flow in a connected artery, the change in pressure may cause blood to flow forward or backward in the circle of Willis to compensate. In a situation when the arteries on one side have reduced blood flow, this mechanism could also help blood flow from one side of the brain to the other. In an emergency (such as a stroke), this can reduce the damage or aftereffects of the event. Importantly, the circle of Willis does not actively carry out the function, but the natural shape of the circle and the way that pressure acts in the area simply allow for bidirectional blood flow when necessary. Structural differences in the circle of Willis are common. The classic, complete anatomy of a circle of Willis is only apparent in a minority of cases. It is more common to see one of a few variations in the structure of the circle of Willis. One of the studies noted that about 70% of people may have an incomplete circle of Willis. An incomplete circle of Willis can take a few different forms. Another study showed that at least one variation was present in the circle of Willis in 54% of cases. The most common structural difference was the absence of a posterior communicating artery connecting to the circle of Willis. Other variations are also common, for example, a change in the anterior communicating artery can make the circle of Willis incomplete. Other different changes are possible including fenestration and duplication. Fenestration occurs when a single vessel divides into two channels and then again becomes one channel later. Duplication means that there are two distinct arteries where there normally is one. In rarer cases, people can have an azygos anterior cerebral artery (ACA), that occurs when the two ACA blood vessels fuse into one. Genetics can play a role in certain forms of an incomplete circle of Willis structures, so it can be more common among family members. Several diseases and conditions have an association with the circle of Willis, including: Stroke - The structure and function of the circle of Willis can protect against stroke in people who have a complete circle of Willis because the complete circle allows blood to go from one side of the brain to the other, even when blockages or thinning vessels occur. The process in which a change in pressure from a blockage/thinning vessel could cause blood to flow backward through the circle of Willis and still reach similar areas of the brain or other important structures is called collateral circulation. It can protect a person from major events or a lack of oxygen in the brain due to impaired blood flow. Collateral circulation is not a guaranteed effect, it can only occur in people with a mostly or fully complete circle of Willis. Aneurysms - The circle of Willis is a very common place for intracranial aneurysms to occur. An estimated 85% of all intracranial aneurysms occur here. Aneurysms refer to arteries that bulge/balloon out. The major risk with aneurysms is rupturing, which causes bleeding in the brain. A ruptured aneurysm can cause an extremely severe headache alongside other symptoms, such as vision problems, light sensitivity, and a stiff neck. Subclavian steal syndrome - This is a rare condition that may go unnoticed because it is largely asymptomatic. It occurs when there is not enough blood supply to an arm through the subclavian artery. When it happens, extra blood flows through the circle of Willis to make up for the lack of blood supply, but this can result in insufficient blood going to the brain. If symptoms do occur, they can appear due to an ischemic event. Some possible symptoms of subclavian steal syndrome include numb arm or arm pain, general fatigue, cold skin from lack of blood supply, and dizziness when exercising.13 - Cerebrospinal fluid (CSF) is an ultrafiltrate of plasma contained within the ventricles of the brain and the subarachnoid spaces of the cranium and spine. It performs vital functions, including providing nourishment, waste removal, and protection to the brain. Adult CSF volume is estimated to be 150 ml, with a distribution of 125 ml within the subarachnoid spaces and 25 ml within the ventricles. CSF is predominantly secreted by the choroid plexus with other sources playing a more poorly defined role. Its secretion varies between individuals in the adult population, usually ranging from 400 to 600 ml per day. In the average young adult, the constant secretion of CSF contributes to complete CSF renewal four to five times per 24-hour period. The reduction of CSF turnover may contribute to the accumulation of metabolites seen in aging and neurodegenerative diseases. The composition of CSF is strictly regulated, and any variation can be useful for diagnostic purposes. 70-80% percent of CSF production is via a network of modified ependymal cells known as the choroid plexus (CP). The CP is a highly specialized, simple, cuboidal epithelium continuous with ependymal cells lining the ventricles of the brain. This simple cuboidal epithelium surrounds clusters of fenestrated capillaries allowing for the filtration of plasma. CP cells have dense microvilli present on their apical surface. They are interconnected via tight junctions, creating a blood-CSF barrier that helps control the composition of CSF. The blood-CSF barrier also serves to regulate the environment of the brain because there is no appreciable barrier between the CSF and the extracellular space of the brain (ECSB). Larger substances such as cells, protein, and glucose can not pass, but ions and small molecules such as vitamins and nutrients can pass into the CSF relatively easily. Water is allowed passage through the CP epithelium via epithelial AQP1 channels. Substances that may not pass through the blood-CSF barrier, but are needed by the brain can be actively synthesized by or actively transported through the CP epithelial cells into the CSF. A 5-mV lumen positive voltage potential is present across CP epithelial cell membranes. This electrical potential difference pulls sodium, chloride, and bicarbonate ions from the plasma into the CSF, creating an osmotic gradient that then drives the movement of water into the CSF. Compared to plasma, CSF has a higher concentration of sodium, chloride, and magnesium, but a lower concentration of potassium and calcium. Unlike plasma, CSF has only trace amounts of cells, protein, and immunoglobulins. No cells can pass through the blood-CSF barrier, although small numbers of white blood cells are usually introduced to the CSF indirectly. The normal cell count of CSF is generally lower than 5 cells/ml. The composition of CSF is kept constant, which provides a stable intraventricular environment, critical for maintaining normal neuronal function. CSF assists the brain by providing protection, nourishment, and waste removal. CSF provides hydromechanical protection of the neuroaxis through two mechanisms. First, CSF acts as a shock absorber, cushioning the brain against the skull. Second, CSF allows the brain and spinal cord to become buoyant, reducing the effective weight of the brain from its normal 1,500 grams to a much lesser 50 grams. The weight reduction lessens the force applied to the brain parenchyma and cerebral vessels during mechanical injury. Another function of CSF is to maintain homeostasis of the interstitial fluid of the brain, a stable environment for brain parenchyma is imperative for maintaining normal neuronal function. The major conduit of nutrient supply to the brain is the CP-CSF-ECSB nexus. Substrates needed by the brain are transported from the blood, through the CP, into the CSF, and then diffuse into the ECSB for transportation to their sites of action within the brain. CSF assists in the removal of brain metabolism waste products, such as peroxidation products, glycosylated proteins, excess neurotransmitters, debris from the lining of the ventricles, bacteria, viruses, and otherwise unnecessary molecules. Accumulation of such unnecessary molecules, seen in aging and some neurodegenerative diseases, interferes with the neuronal functioning of the brain. The disruption of cerebral physiology experienced with the disruption of the hydrodynamics or composition of CSF suggests the importance of CSF functioning. CSF is continuously secreted with an unchanging composition, functioning to maintain a stable environment within the brain. CSF is propelled along the neuroaxis from the site of secretion to the site of absorption, mainly by the rhythmic systolic pulse wave within the choroidal arteries. Lesser determinants of CSF flow are frequency of respiration, posture, venous pressure of the jugular vein, the physical effort of the individual, and time of day. CSF is secreted by the CPs located within the ventricles of the brain, with the two lateral ventricles being the primary producers. CSF flows throughout the ventricular system unidirectionally in a rostral to caudal manner. CSF produced in the lateral ventricles travels through the interventricular foramina to the third ventricle, through the cerebral aqueduct to the fourth ventricle, and then through the median aperture, also known as the foramen of Magendie, into the subarachnoid space at the base of the brain. Once in the subarachnoid space, the CSF begins to have a gentle multidirectional flow that creates an equalization of composition throughout the CSF. The CSF flows over the surface of the brain and down the length of the spinal cord while in the subarachnoid space. It leaves the subarachnoid space through arachnoid villi found along the superior sagittal venous sinus, intracranial venous sinuses, and around the roots of spinal nerves. Arachnoid villi are protrusions of arachnoid mater through the dura mater into the lumen of a venous sinus. A 3 to 5 mmHg pressure gradient between the subarachnoid space and venous sinus pulls CSF into the venous outflow system through the arachnoid villi to help with its absorption. CSF may also enter the lymphatic system via the nasal cribriform plate or spinal nerve roots. The clearance of CSF is dependent upon the posture of the individual, pressure differentials, and pathophysiology. Lumbar puncture (LP also known as spinal tap), is a commonly performed invasive procedure in which CSF is removed from the subarachnoid space and is used in the measurement of intracranial pressure and the sampling of CSF. It is commonly indicated in the evaluation of acute headaches and infections of the central nervous system. During an LP, the patient is placed in the lateral recumbent position. A sterile spinal needle is then slowly inserted between vertebrae, usually at the level of L3/4 or L4/5, into the subarachnoid space. Needle insertion may be guided by fluoroscopy or ultrasound to improve success rates and reduce the incidence of trauma. Once CSF begins to flow through the needle, it is collected serially into four sterile tubes. Once collected, CSF can be analyzed for abnormally present or elevated CSF components, aiding in diagnosis. For example, the presence of xanthochromia, a yellow-orange discoloration of CSF caused by red blood cell degeneration, indicates the possibility of a subarachnoid hemorrhage. Contraindications of LP include raised intracranial pressure, bleeding disorders, and local skin infection. The procedure is relatively safe with seldom serious complications. Complications of LP include infection, bleeding, radicular pain, or cerebral herniation. The most common complication is a post-LP headache with symptoms beginning within 24 hours of the procedure and often resolving by day 10. Subarachnoid Hemorrhage (SAH) is the leakage of blood into the subarachnoid space where it mixes with CSF. Trauma is the most common cause of SAH with 80% of nontraumatic SAHs resulting from aneurysm rupture. Other nontraumatic causes of SAH include arteriovenous malformations and vasculitis. Spontaneous SAH has a low incidence, with only 30,000 cases worldwide annually. In this diagnosis a non-contrast head CT is useful. CT has high sensitivity after hemorrhage, but sensitivity decreases as time passes. After a negative CT, an LP should follow to rule out SAH. An LP for SAH is positive when erythrocytes are present in tubes 1 and 4, or xanthochromia is visible. 14 Xanthochromia is the presence of bilirubin in the cerebrospinal fluid and is sometimes the only sign of an acute subarachnoid hemorrhage. 15 Management of SAH consists of reducing risks of re-bleeding and avoiding any secondary brain injuries. 14 - The prognosis for subarachnoid hemorrhage depends on its cause, severity, and the presence of other complications or injuries. It’s a severe condition, half of people who have subarachnoid hemorrhage experience sudden death. Of those who make it to a hospital one third die in the hospital, one-third survive with a disability, and one-third return to their normal function. 24 Serious complications can occur, after a subarachnoid hemorrhage. Swelling in the brain, or hydrocephalus is one of the potential complications. Subarachnoid hemorrhage can also irritate and damage the brain's other blood vessels, causing them to tighten (this reduces blood flow to the brain). As blood flow becomes affected, another stroke can result, leading to even further brain damage. In serious cases, the bleeding may cause permanent brain damage, paralysis, or coma. 12 Possible immediate complications of SAH include: Seizures - Blood can irritate the cerebral cortex and result in a seizure. Only a small percentage of patients with SAH go on to have epilepsy (a seizure disorder). Doctors may consider using preventive anti-epileptics in the immediate time after the hemorrhage. But long-term anti-epileptic use is not recommended (with some exceptions based on individual risk factors), due to the risks of side effects. 27 Vasospasm (a brain blood vessel narrows, blocking blood flow)- The most common complication following subarachnoid hemorrhage. The risk of vasospasm occurs later than the risk of rebleeding. The risk correlates with the extent of the initial bleed and with Fisher's classification. It preferentially affects young women. Degradation and lysis of extravascular blood clots within the cerebral fluid lead to the release of vasoactive mediators, which cause cerebral vasoconstriction leading to a fall in cerebral blood, flow. It may be followed by the development of a cerebral hypoperfusion area with a risk of cerebral infarction, which can be fatal. A warning sign for this is the development of a focal neurological deficit on day 3 after a subarachnoid hemorrhage. Clinical symptoms are occasionally more silent and the development of fever in the absence of other pointers towards infection, or of sweating, agitation, or confusion should also suggest a diagnosis of vasospasm. The diagnosis should be confirmed radiologically if this is suspected clinically. Transcranial Doppler ultrasound is used first line and shows increased arterial circulatory systolic and mean velocities in the spastic artery. The increase in middle cerebral artery circulation velocities is proportional to the severity of the vasospasm. A mean velocity of between 80 and 120 cm/s may represent mild vasospasm and with mean velocities of up to 130 cm/s arteriography usually shows moderate vasospasm. Using a cutoff of 130 cm/s, the specificity of transcranial Doppler ultrasound to detect spasm is 96%, with a positive predictive value of 87%. A mean velocity of over 200 cm/s is suggestive of severe vasospasm liable to cause cerebral ischemia. It is a rapid rise in velocities rather than the absolute value of the systolic peak, which is the poor prognostic indicator. A middle cerebral artery systolic/extracranial artery systolic velocity ratio (the Lindegaard index) of over 3 is also used to assess vasospasm. An increase in velocity due to vasospasm may be masked by concomitant raised intracranial pressure, although the increase in resistance indices should generally draw radiologists’ attention and allow this to be taken into account in the interpretation. Transcranial Doppler ultrasound has limitations: the vessels in which the highest velocities are seen are not necessarily located in territories that correspond to the symptoms of ischemia; symptomatic ischemia is not always manifest in the arteries located close to the areas where the greatest bleed has occurred and distal cerebral arteries are difficult to examine. Given these limitations, cerebral MRI or cerebral CT angiography with perfusion-weighted images can confirm the actual diagnosis and exclude the differential diagnoses, which include acute hydrocephalus. Images show arteries in spasm, which are tapered and responsible for a greater, or lesser area of cerebral hypoperfusion with raised mean transit time (MTT) and time to peak (TTP). This may be combined with greater or lesser areas of cerebral ischemia, which are often punctiform and diffuse and affect the distal arterial and junctional areas although the presence of arterial spasm is not necessarily synonymous with distal ischemic injury and vice versa. The treatment for vasospasm is initially pharmacological escalating therapy with intravenous nimodipine and maintaining high blood pressure. Hypervolemia is still debated. If a patient is resistant to pharmacological treatment, an endovascular approach may be offered involving repeated intra-arterial administration several days in succession close to the artery in spasm, nitrates, and possibly arterial balloon angioplasty. 28 Re-bleeding (or hemorrhaging again after initial treatment) - Rebleeding is the most serious acute complication and generally occurs in the first three days after the initial bleed, with an estimated risk of up to 9 to 17% in the initial hours. It is often associated with a poorer prognosis and higher Fisher grade. Occlusion of a ruptured intracranial aneurysm is therefore a treatment emergency in the initial 12 to 24 hours to reduce the major risk of rebleeding. Coiling was shown to be effective compared to surgery for ruptured aneurysms and had an estimated risk of dependency and death of 23.7% compared to 30.6%. Insertion of an external ventricular shunt increases the risk of rebleeding. 28 Hydrocephalus - Caused by the build-up of cerebrospinal fluid and blood between the brain and skull, which can increase the pressure on the brain. 12 Sometimes blood clots from the subarachnoid hemorrhage can become lodged in one of the important natural CSF drainage sites. Normally, CSF is produced in the ventricles of the brain and then travels out through small openings known as foramina. CSF is also re-absorbed into the bloodstream via small valves, called arachnoid granulations, which are located on the surface of the brain. If there is a blockage in one of the channels of the brain or the arachnoid granulations, the CSF is still produced but has nowhere to go. The result is an increase in pressure inside the ventricles of the brain, which is known as hydrocephalus. The pressure spreads to the brain and skull. Increased intracranial pressure can lead to decreased consciousness and coma. If left untreated, the brain can be pushed through tight regions like the opening at the base of the skull, resulting in death. To prevent this pressure build-up, neurosurgeons can place a shunt into the skull to drain out excess CSF. Lumbar drainage may also be used in the treatment of a type of hydrocephalus called communicating hydrocephalus. 27 Acute hydrocephalus - A sudden dilatation of the ventricular system due to obstruction to the flow of cerebrospinal fluid caused by blood degradation products when the ventricle is breached and is seen in up to 20% of patients. The risk is proportional to the extent of the initial bleed although subarachnoid hemorrhage with a low initial Fisher grade may also be complicated by acute hydrocephalus. This worsens the prognosis by increasing the incidence of raised intracranial pressure in addition to the cerebral edema caused by the subarachnoid hemorrhage itself. It is extremely important to identify ventricular dilatation from the point of early treatment onwards. It begins with dilatation of the temporal horns, which is easy to identify in the absence of subcortical atrophy. Before endovascular treatment to exclude the aneurysm, an external ventricular shunt may be inserted on an urgent basis by the neurosurgeons. Classically this is performed routinely for Fisher grade 3 or 4 subarachnoid hemorrhages and is considered depending on clinical symptoms for Fisher grades 1 or 2. Its purpose is to release the raised intracranial pressure and prevent the risk of neurological deterioration. A shunt catheter clamp test is performed on D15 before it is possibly removed. 28 Chronic complication (chronic hydrocephalus) - Occurs late after the initial subarachnoid hemorrhage. The classical symptoms are Adam and Hakim's triad of walking difficulties, sphincter disturbances and cognitive disorders, disorientation, and confusion. It is because of the partitioning in the arachnoid space, which prevents normal reabsorption of cerebrospinal fluid and causes dilatation of the ventricular system. An unenhanced cerebral CT should be performed to look for ventricular dilatation if a patient develops neurological problems late after a subarachnoid hemorrhage. Depending on age and clinical signs, the treatment of chronic hydrocephalus involves a depletional lumbar puncture or insertion of a ventricular peritoneal shunt by neurosurgeons. Studies have also shown that late cognitive or behavioral complications may develop. 25% of the patients develop moderate depression after a subarachnoid hemorrhage and several years after the hemorrhage, approximately 50% of survivors report that they think that their personality has changed, generally for the worse, the cases reported being mostly weakness, excessive irritability, memory difficulties, daytime drowsiness, and insomnia. 28 Increased intracranial pressure - A clinical condition that is associated with an elevation of the pressures within the cranium. The pressure in the cranial vault is normally less than 20 mm Hg. The cranium is a rigid structure that contains three main components that are in a state of constant fixed volume: brain, cerebrospinal fluid, and blood. Any increase in the volume of its contents will increase the pressure within the cranial vault. An increase in the volume of one component will result in a decrease in the volume of one or two of the other components. The clinical implication of the change in volume of the component is a decrease in cerebral blood flow or herniation of the brain. 30 Brain herniation – Occurs when something inside of your skull produces pressure that moves brain tissues from one space in the skull to another through various folds and openings.31 Cerebral infarction (ischemic stroke) - Occurs as a result of disrupted blood flow to the brain due to problems with the blood vessels (narrowing/occlusion) that supply it. A lack of adequate blood supply to brain cells deprives them of oxygen and vital nutrients which can cause parts of the brain to die off. 29 Acute ischemic lesions - Acute massive cerebral edema is a rare complication, of poorly understood pathophysiology, which may result in diffuse cortical ischemic injury leading to death within hours after the subarachnoid hemorrhage. This usually affects young people regardless of the severity of the initial bleed and involves a sudden-onset diffuse cerebral edema with abrupt accelerated phase raised intracranial pressure. It can be demonstrated by inserting an intracranial pressure sensor. Cerebral MRI with diffusion-weighted images can help in the diagnosis of a patient presenting with sudden-onset abnormalities of consciousness. Treatment is with a combination of medical therapy for the edema and neurosurgery with the insertion of an external ventricular shunt, but in most cases, this is not sufficient to improve the prognosis. 28 Death 24 Subarachnoid hemorrhage (SAH) can cause brain damage, which can lead to long-term or even permanent issues. Possible long-term complications of SAH include: Physical issues - SAH can lead to physical difficulties, such as drowsiness and fatigue, numbness or weakness in parts of your body, difficulty swallowing, and loss of balance. Cognitive (thinking) issues - SAH can lead to cognitive dysfunction, including memory problems, difficulty concentrating and difficulty planning and performing complex tasks. Speech difficulties - SAH can cause your speech to become slurred or slowed. You may also have difficulty finding the right words to express yourself. Mental health conditions - SAH is a major life event. This can lead to mental health conditions, such as depression, generalized anxiety and post-traumatic stress disorder (PTSD). These long-term complications can be managed and treated with several different types of therapies, including physical therapy, occupational therapy, speech therapy, psychotherapy (talk therapy), and certain medications may also help. 24 Non-neurological complications following the SAH include electrocardiographic repolarization abnormalities, occasionally genuine findings of myocardial distress with raised troponins, and the Tako-Tsubo syndrome with acute respiratory injury (acute pulmonary edema, ARDS). Regular electrolyte monitoring is required as serum sodium and potassium abnormalities are common as well. 28

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London Tipton

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- MRI scanning, ultrasonography, CT angiography, MR perfusion (Omid Shafaat and Houman Sotoudeh) (“Using Ultrasound to Detect Intracranial Hemorrhage - Explore Sound”). - Warfarin is an oral anticoagulant usually used to treat and prevent blood clots (Patel et al.). It is a drug commonly described as a “blood thinner” (Patel et al.). This could have worsened the bleed into the brain, as the blood leakage did not have the ability to clot. More blood got into the brain and worsened the damage. The fact that the blood of the patient cannot clot naturally worsens his prognosis and decreases his chance of survival. - The priority in treating haemorrhagic stroke is reducing the bleeding or stopping it entirely by boosting blood clotting (“Hemorrhagic Stroke: What It Is, Causes, Symptoms & Treatment.” ). Blood pressure has to be lowered as well. The treatment depends on severity of the stroke, sometimes surgery will be necessary (“Hemorrhagic Stroke: What It Is, Causes, Symptoms & Treatment.” ). If swelling of the brain tissue occurs, medication has to be administered to reduce the swelling and decrease the pressure that has built up in the brain as a result of this swelling (“Can a Person Survive a Hemorrhagic Stroke?”). Surviving a stroke depends on its intensity, unfortunately a large portion of patients die within a few days of experiencing a stroke (“Can a Person Survive a Hemorrhagic Stroke?”). Chances of survival are increased if the patient receives immediate medical attention. Recovering from a stroke is possible, some survivors are able to live longer than five year after experiencing a stroke, but the recovery process is long and slow (“Can a Person Survive a Hemorrhagic Stroke?”).

- There are five types of stroke (“Types of Stroke and Treatment”). Ischemic stroke occurs when a blood clot blocks an artery supplying oxygen to the brain (“Stroke - Symptoms and Causes”). Haemorrhagic stroke is caused by a bleed from an artery into the brain (“Hemorrhagic Stroke | Cedars-Sinai”). When blood supply to the brain stem is stopped, brain stem stroke occurs (“Brain stem stroke”). A transient ischaemic attack happens when a stroke only lasts a few minutes, by brief brain blood supply interruption (“Transient Ischemic Attack (TIA)”). Cryptogenic stroke is defined as cerebral ischaemia of unknown or obscure origin (Finsterer). - Some of the risk factors for haemorrhagic stroke include gender, age, high blood pressure (hypertension), excessive alcohol intake, smoking, and having AVM (arteriovenous malformations) (“Hemorrhagic Stroke | Neurology | Mercy Health”). The patient in this case study was a smoker and suffered from high blood pressure.

- The scan shows a CT scan of the cerebral cortex of the brain. The arrow pointing at the area of the brain that appears whit in the scan is pointing towards a haemorrhage. Haemorrhages appear white in colour on brain CT scans. The arrow pointing to the slightly darker grey matter shows oxygen deprived neurons. - Haemorrhagic stroke is caused by a weakened blood vessel rupturing and bleeding into the surrounding brain (Reem Alkahtani). Blood accumulates and creates pressure on the surrounding brain tissue (Kuriakose and Xiao). As can be seen on the CT scan, the bleed into the brain is very large and can result in a lot of brain damage.

- The most likely diagnosis would be that the patient is suffering from a stroke. The most common symptoms include weakness or numbness in one side of the body (the “weird smile” identified by the patient’s wife), trouble speaking (also displayed by the patient), problems with vision, and problems with walking (“Stroke - Symptoms and Causes.”). The patient also has very high blood pressure, which might have caused a brain bleed (rupturing of a blood vessel) and resulted in the stroke (“Stroke - Symptoms and Causes.”). - Dysarthria is a medical term used to describe speech difficulties due to muscle weakness (“Dysarthria in Adults.”). Dysarthria can be flaccid (caused by muscle weakness), spastic (caused by muscle rigidity), ataxic (caused by muscle weakness and reduced movement control), hypokinetic (caused by reduced movement), and hyperkinetic (caused by excessive muscle movement) (“Dysarthria in Adults.”). - Act FAST (Jones): F – Face drooping A – Arm weakness S – Speech difficulty T – Time (immediate medical attention is necessary) This mnemonic tool can be used to identify stroke in patients and ensure they get immediate medical help (Jones).

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Ahmad Farroukh

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Intravenous antibiotics should be administered to the patient and she should be kept in the intense care unit to be under medical supervision and tested further to ensure the diagnosis is correct (“Meningitis - Diagnosis and Treatment - Mayo Clinic”).

-Bacterial meningitis is caused by several strains of bacteria including Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, and Haemophilus influenzae (“Bacterial Meningitis.”). Acute bacterial meningitis must be treated immediately with administering intravenous antibiotics and sometimes corticosteroids. This reduces risks of complications, such as brain swelling and seizures (“Bacterial Meningitis.”). It also helps to ensure recovery. The type of antibiotic used depends on the type of bacteria causing the infection (“Bacterial Meningitis.”). -If the patient has been travelling abroad other diseases such as Tick-Borne Encephalitis, Meningococcal meningitis, and Eosinophilic meningitis should be considered (Han and Zunt).

The CSF glucose concentration is very low (“CSF Glucose”), signifying Hypoglycorrhachia which is often associated with bacterial, fungal, or tuberculous meningitis (Chow). It is often accompanied with high CSF pressure (intercranial hypertension) which is also the case in the patient (“Idiopathic Intracranial Hypertension”). Turbid CSF indicates an elevated presence of white or red blood cells, microbes, or an increase in protein levels. Since the white blood cell count was measured by blood tests and the results showed their elevated count, we can assume that the CSF is turbid due a large number of white blood cells (“Cerebrospinal Fluid (CSF) Testing”). All of these signs point to a meningitis infection.

-Transferring the patient to an intense care unit, providing her with medication to lower her fever and giving her an IV with nutrients and water could partially stabilise her. Further tests would have to be administered to get to the diagnosis. -Blood tests (checking for bacteria or viruses, as well as the white blood cell count) should be done as well as an analysis of the cerebrospinal fluid. Something is clearly going on in the central nervous system, the brain more specifically, of the patient because her score on the Glasgow coma scale (Jain and Iverson) and the Mini-mental state examination are not high. The Mini-mental state examination is especially low, showing that there is cognitive impairment going on. A CT scan of the brain could be done as well, a visual image of what is going on in the brain would be of good use in determining as to what is going on (“Treatment - Meningitis”). I would also check if the patient was administered a vaccine against some types of bacterial meningitis (“Meningitis”). -Due to the fact that Amanda is young she will be able to make a full recovery. Only one in five people have long-lasting effects after surviving an episode of bacterial meningitis (“Meningitis Symptoms, Diagnosis, and Treatments | Precision Neurology”).

10

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Treatment of a patient suffering from SAH begins with their placement to an intense care unit. A draining tube to relive brain pressure is needed, as well as medications to decrease brain swelling, medication to manage blood pressure, medication to prevent artery spasms, and medication to prevent or treat seizures (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”). Surgery will be necessary to remove large blood collections and to repair the aneurysm if the rupture is caused by one (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”).

- Hypertension can be one of the causes for non-traumatic bleeding. This can result in ruptures of intercranial aneurysms (“Nonaneurysmal subarachnoid haemorrhage”). Bleeding can also be caused by arteriovenous malformation (a tangle of blood vessels connecting the arteries and veins in the brain), carotid artery dissection (the separation in the layers of the carotid artery in the neck), or vascular inflammation that affects the central nervous system (“Subarachnoid Hemorrhage”). - Risk factors: Hypertension, smoking, family history, alcohol, sympathomimetic drugs, oestrogen deficiency (“Subarachnoid Hemorrhage”)

Symptoms confirming SAH diagnosis: The patient is light-sensitive, has a severe headache (different from a normal headache) that arrived with a sudden onset, experiences vomiting and sudden weakness, and has a stiff neck (“Subarachnoid Hemorrhage”).

- Inner layer – Pia mater: The innermost membrane, directly adherent to the surface of the spinal cord and the brain, following all its convolutions. Its composition includes delicate connective tissue and miniscule blood vessels. It is connected to the arachnoid by a sub-arachnoid space, filled with cerebrospinal fluid (David Cortés Santamarta and González‐Martínez). Middle layer – Arachnoid: A thin transparent membrane lacking its own innervation and blood supply. It is connected to the Dura mater by the sub-dural space in which fluid can connect (Gülgün Kayalıoğlu). Outer layer – Dura mater: A tough, thick, and fibrous structure containing a rich vascular network, extensive nerve supply, and lymphatic drainage canals. To its outer side is located the epidural space, which consists of epidural fat, the venous plexus, and segmental arteries(Gülgün Kayalıoğlu). - The circle of Willis is an anastomotic ring of arteries that can be found at the base of the brain (“Arteries of the Brain II.”). It connects two major arterial systems of the brain (“Arteries of the Brain II.”). It is formed by four paired vessels and one unpaired vessel with numerous branches supplying the brain (Gupta). Its main function is to provide collateral blood supply to the brain (between the anterior and posterior arterial systems) (Gupta). Moreover, it provides an alternate pathway for blood to flow form between the right and left cerebral hemispheres (Gupta). - Cerebrospinal fluid (CSF) is a clear and colourless fluid flowing in the brain and the spinal cord. Its function is to provide nutrition, waste removal, and protection of the Central nervous system. In a patient diagnosed with SAH we would expect the CSF to be yellow in colour (Xanthochromia) which is caused by a haemoglobin catabolism (Dugas et al.). Xanthochromia can be identified by the presence of bilirubin in CFS (Dugas et al.). - Long-term complications for patients with SAH include physical complications such as fatigue and drowsiness, difficulty swallowing, weakness or numbness in certain body parts, or loss of balance (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”). Speech can become slowed or slurred and the patient may have difficulties finding words to express themselves (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”). SAH can result in cognitive dysfunctions, problems with memory and concentration, difficulty with planning and performing complex functions (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”). Mental health effects may include the development depression, anxiety, or PTSD (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”).

11

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Treatment of a patient suffering from SAH begins with their placement to an intense care unit. A draining tube to relive brain pressure is needed, as well as medications to decrease brain swelling, medication to manage blood pressure, medication to prevent artery spasms, and medication to prevent or treat seizures (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”). Surgery will be necessary to remove large blood collections and to repair the aneurysm if the rupture is caused by one (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”).

Hypertension can be one of the causes for non-traumatic bleeding. This can result in ruptures of intercranial aneurysms (“Nonaneurysmal subarachnoid haemorrhage”). Bleeding can also be caused by arteriovenous malformation (a tangle of blood vessels connecting the arteries and veins in the brain), carotid artery dissection (the separation in the layers of the carotid artery in the neck), or vascular inflammation that affects the central nervous system (“Subarachnoid Hemorrhage”).

Symptoms confirming SAH diagnosis: The patient is light-sensitive, has a severe headache (different from a normal headache) that arrived with a sudden onset, experiences vomiting and sudden weakness, and has a stiff neck (“Subarachnoid Hemorrhage”).

Long-term complications for patients with SAH include physical complications such as fatigue and drowsiness, difficulty swallowing, weakness or numbness in certain body parts, or loss of balance (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”). Speech can become slowed or slurred and the patient may have difficulties finding words to express themselves (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”). SAH can result in cognitive dysfunctions, problems with memory and concentration, difficulty with planning and performing complex functions (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”). Mental health effects may include the development depression, anxiety, or PTSD (“Subarachnoid Hemorrhage (SAH): Symptoms & Treatment.”).

12

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antiinflammatories, anti-clotting drugs

heart attack, heart burn

heart attack

blood pressure

13

Nada Beltagui

2

Prescribe Ibuprofen or Paracetamol for pain relief during headache episodes. If migraines are confirmed, prescribe Sumatriptan for acute migraine attacks. Encourage lifestyle changes such as reducing caffeine intake, maintaining a regular sleep schedule, and managing stress.

Migraine, Tension-Type Headache, Cluster Headache, Sinusitis, Medication Overuse Headache

Migraine

Neurological Examination, MRI or CT Scan, Sinus X-Ray, Blood Tests

14

Nada Beltagui

2

Prescribe Ibuprofen or Paracetamol for pain relief during headache episodes. If migraines are confirmed, prescribe Sumatriptan for acute migraine attacks. Encourage lifestyle changes such as reducing caffeine intake, maintaining a regular sleep schedule, and managing stress.

Migraine, Tension-Type Headache, Cluster Headache, Sinusitis, Medication Overuse Headache

Migraine

Neurological Examination, MRI or CT Scan, Sinus X-Ray, Blood Tests

15

Nada Beltagui

2

Prescribe Ibuprofen or Paracetamol for pain relief during headache episodes. If migraines are confirmed, prescribe Sumatriptan for acute migraine attacks. Encourage lifestyle changes such as reducing caffeine intake, maintaining a regular sleep schedule, and managing stress.

Migraine, Tension-Type Headache, Cluster Headache, Sinusitis, Medication Overuse Headache

Migraine

Neurological Examination, MRI or CT Scan, Sinus X-Ray, Blood Tests

16

Rylee Rosenlieb

2

Prescribe Ibuprofen or Paracetamol for pain relief during headache episodes. If migraines are confirmed, prescribe Sumatriptan for acute migraine attacks. Encourage lifestyle changes such as reducing caffeine intake, maintaining a regular sleep schedule, and managing stress.

Migraine, Tension-Type Headache, Cluster Headache, Sinusitis, Medication Overuse Headache

Migraine

Neurological Examination, MRI or CT Scan, Sinus X-Ray, Blood Tests

17

Nada Beltagui

2

Prescribe Ibuprofen or Paracetamol for pain relief during headache episodes. If migraines are confirmed, prescribe Sumatriptan for acute migraine attacks. Encourage lifestyle changes such as reducing caffeine intake, maintaining a regular sleep schedule, and managing stress.

Migraine, Tension-Type Headache, Cluster Headache, Sinusitis, Medication Overuse Headache

Migraine

Neurological Examination, MRI or CT Scan, Sinus X-Ray, Blood Tests

18

Nada Beltagui

2

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20

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common for people

period

rest

21

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diet

cramps, period

cramps

ultrasound

22

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anorexia, thyroid dysfunction

thyroid dysfunction

blood tests

23

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Immediate empiric antibiotic therapy with ceftriaxone, along with isolation precautions and management of coagulopathies.

Meningococcal Meningitis.

Meningococcal Meningitis.

Blood cultures, complete blood count (CBC), lumbar puncture, CNS imagining (CT).

24

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(was not requested in the questions) - Creutzfeldt-Jakob Disease (CJD), Lewy Body Dementia.

Creutzfeldt-Jakob Disease (CJD).

(was not requested in the questions)

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low blood pressure, diarrhea

low blood pressure

blood test

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psychologist

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