24
Management of Patients with Central Nervous System Infections
ACUTE BACTERIAL MENINGITIS
Meningitis is inflammation of the meninges; more specifically the arachnoid and pia membranes and the intervening subarachnoid space. Bacterial meningitis is inflammation caused by bacterial infection. It is associated with high morbidity and mortality and requires urgent medical intervention to minimise the impact of the disease. Viral meningitis generally has a more benign clinical course and rarely requires hospitalisation. Meningitis can also be caused by other pathogens, e.g. fungi or parasites, however these are rare and most often affect people who are immunocompromised.
AETIOLOGY AND EPIDEMIOLOGY
The most common causes of acute community acquired bacterial meningitis are Neisseria meningitidis and Streptococcus pneumoniae. Mycobacterium tuberculosis meningitis has a more chronic presentation and is presented at the end of the section on meningitis.
Neisseria meningitidis (meningococcus) is the most common cause of acute bacterial meningitis in the UK. It mainly affects babies and children under five years. Older teenagers are the second most at risk group. There are a number of known serogroups (strains) of meningococcal bacteria, the most common of which are Neisseria meningitidis serogroup B and C. The introduction of the MenC vaccine has led to a decline in the number of cases of serogroup C and consequently the majority of cases are now caused by MenB (Meningitis Research Foundation, 2009). A meningococcal group B vaccine is currently going through phase III trials.
Meningococci are spread through the exchange of saliva and other respiratory secretions during coughing, sneezing and intimate kissing. Close prolonged contact is usually required to transmit the bacteria (Health Protection Agency, 2009). People harmlessly carry meningococci in the nasopharynx and it is not known why some people develop the disease. Factors such as a compromised immune system can provide an opportunity for the bacteria to overcome the body’s immune defences to cause disease. Meningococci can cause meningitis and/or septicaemia. Most people will have symptoms of both. When meningococci cause meningitis and/or septicaemia it is called meningococcal disease. Meningococcal disease affects around 2,000 people in the UK and Ireland every year (Meningitis Research Foundation, 2009).
The bacterium Streptococcus pneumoniae (pneumococcus) is the second most common cause of meningitis in the UK, but accounts for the majority of cases in adults. There are 90 serotypes of this bacterium. Similar to meningococci, these bacteria can live in the nasopharynx usually without causing disease. A compromised immune system, e.g. HIV, alcoholism, splenectomy, chronic otitis media, sickle cell disease, are particular factors that predispose people to pneumococcal meningitis.
The pneumococcal conjugate vaccine was introduced to the childhood immunisation programme in the UK in September 2006 (Donovan and Blewitt, 2009). It protects against seven of the most common serotypes and has led to a subsequent reduction in childhood cases. The efficacy of the vaccine has not been proven in older adults (Hayderman et al., 2003).
A CSF leak due to head injury or neurosurgery allows direct invasion of the meninges by bacteria. Staphylococcus aureus is the most common cause following craniotomy. S. pneumoniae and gram negative bacilli such as Escherichia coli (E. coli), Pseudomonas spp and Klebsiella spp are the most common pathogens to cause meningitis following a recent open skull fracture (Hankey and Wardlaw, 2008).
Less common causes of acute bacterial meningitis
Before the introduction of the Haemophilus influenzae type b (Hib) vaccine in the 1990s, Hib was the most common cause of meningitis in children under four years. It is now a rare cause in all age groups. The Hib vaccine is being introduced in developing countries, however the number of cases world wide and associated deaths still remains unacceptably high. As a consequence of routine vaccination programmes in the developed world, e.g. Hib and MenC, the incidence of meningitis in babies has decreased, therefore increasing the proportion of patients that are adults (Bonthius and Karacay, 2002).
Listeria monocytogenes is an uncommon cause of meningitis, but occurs especially during pregnancy and in immunosuppressed older adults >55 years. It accounts for less than 5% of cases in adults.
Viral meningitis
Viral meningitis is more common than bacterial, but most cases of viral meningitis are unreported because the disease is often mild and does not require hospitalisation (Donovan and Blewitt, 2009). The most common viruses to cause meningitis are mumps, cytomegalovirus and enteroviruses.
PATHOPHYSIOLOGY
Micro-organisms can enter the cerebrospinal fluid (CSF) directly via the sinuses or through a fracture in the skull. More commonly they enter by the indirect route: the blood stream. The upper respiratory tract is the most common site of colonisation, from where the bacteria overcome the immune defence mechanisms to enter the blood stream. It is not well understood how the bacteria penetrate the blood–brain barrier but once they have entered the CSF the bacteria rapidly multiply because the CSF does not contain the necessary defences to fight bacterial invasion, e.g. immunoglobulins and complement components. The bacteria or their toxins induce a potent inflammatory reaction by the meninges, the ventricles and the brain parenchyma (Boss, 2006). The inflammatory response causes vasodilation and migration of neutrophils into the subarachnoid space. A purulent exudate accumulates in the subarachnoid space which affects the reabsorption of CSF. The exudate blocks the arachnoid villi resulting in communicating hydrocephalus. Inflammation of the outer layer of the brain (cerebritis) typically occurs and abscess formation can result when a localised area of the brain tissue becomes affected. Purulent exudate can also spread into the sheaths of the spinal and cranial nerves. Infection may spread through the walls of blood vessels (vasculitis) causing thrombosis and possible infarction of brain tissue.
The inflammatory response often results in loss of the integrity of the blood–brain barrier with leakage of fluid from the intravascular compartment into the brain (vasogenic oedema) causing an increase in intracranial pressure (ICP). Raised ICP can also occur as a consequence of hydrocephalus.
In meningococcal disease septicaemia can occur with or without meningitis. Septicaemia occurs when the bacteria invade the blood stream and release endotoxins. In such cases shock rapidly occurs. Septicaemia will not be covered in this chapter. Adam and Osborne (2005) comprehensively present the management and nursing care of the patient with septicaemia.
CLINICAL SIGNS AND SYMPTOMS
Early identification is essential to reduce mortality and morbidity (van de Beek et al., 2004) as meningitis can cause death within hours of presentation. However, in the very early stage of meningitis and septicaemia (the prodromal stage) the symptoms may be similar to flu, i.e. headache, pyrexia, nausea, painful joints and lethargy. Symptoms can progress over one to two days but usually develop rapidly, i.e. within a couple of hours. A large prospective study found that the classic triad of stiff neck, fever and altered consciousness were only found to be present in 44% of patients (van de Beek et al., 2004). However 95% of patients presented with at least two signs and symptoms of headache, fever, neck stiffness and alterations in consciousness.
Kernig’s sign and Brudzinski’s sign are present in about half of adults. A positive Kernig’s sign is present when pain is felt in the neck, back and the legs when the examiner flexes the patient’s hip and extends the knee whilst in the supine position. Brudzinski’s sign is when the hips flex to lift the legs in response to the examiner flexing the patient’s neck. Both are indicative of meningeal irritation.
Signs of raised ICP may be present due to hydrocephalus and or cerebral oedema. Altered consciousness may also be a late sign of shock which will occur in meningococcal septicaemia. Seizures develop in approximately 20% of patients. A petechial/purpuric non-blanching rash, i.e. a rash that does not fade when pressure is applied is indicative of meningococcal septicaemia. A glass is used so that the rash can be seen when the pressure is applied. The rash is typically purpuric, (purplish patches or spots caused by extravasation of blood into the skin), and diffuse. A rash is not present in all patients with meningococcal disease. A rash may or may not be present in meningitis caused by other bacteria.
DIAGNOSIS
If, following a thorough physical examination, there is suspicion of meningitis the clinician will perform a lumbar puncture (LP), providing there are no signs suggestive of raised ICP or other contraindications, e.g. bleeding disorders. Performing a LP in a patient with signs of raised ICP is contraindicated as the LP could cause brain herniation (see Chapter 19). When the diagnosis is uncertain a CT scan may be done to exclude other causes and to ensure that it is safe to do a LP. In such cases blood cultures should be taken and empiric antibiotics administered prior to the scan being performed (see: Medical management/treatment). Identification of the causative organism on CSF culture is possible in 70–85% of cases (Hankey and Wardlaw, 2008). CSF findings are of a raised white cell count, raised protein and low glucose level; glucose and protein are relatively normal in cases of viral meningitis. A blood glucose should be sent at the same time as the CSF for comparison. Blood cultures and swabs from the throat and any septic sites should also be sent for culture.
MEDICAL MANAGEMENT AND TREATMENT
Studies have shown that patient outcomes are less favourable when there are delays in the administration of antibiotics (Miner et al., 2001). An algorithm for the early management of bacterial meningitis and meningococcal meningitis was published jointly by the Meningitis Research Foundation (MRF) in collaboration with the British Infection Society (Hayderman et al., 2003). It recommends that patients presenting to a GP with suspected meningitis should receive benzylpenicillin before urgent transfer to an accident and emergency department.
On presentation of any patient to A&E with suspected meningitis, empirical antimicrobial treatment should be administered as soon as the lumbar puncture has been performed and immediately in those who present in a critical condition. Empirical treatment includes ceftriazone or cefotaxime bd and for patients who have an anaphylactic history with penicillins or a rash with cephalosporins, chloramphenicol is used. Amoxicillin 2g 4 hourly is given in addition to ceftriazone to patients suspected of having meningitis caused by Listeria monocytogenes, i.e. patients who are immunosuppressed and those over the age of 55 years. Once the causative organism has been identified from CSF culture the antimicrobial agent may be changed and will be determined by the pathogen that has been isolated. The microbiology services are instrumental for giving advice on the antimicrobial treatment of the disease. Antibiotics are given for a period of 7–14 days, depending on the causative organism and the clinical response to treatment.
Dexamethasone is the only adjunctive therapy to significantly reduce the mortality and morbidity for meningitis (van de Beek et al., 2007). A systematic review (Cochrane review) concluded that dexamethasone should be administered in conjunction with the first dose of antibiotics for all cases of community acquired bacterial meningitis (van de Beek et al., 2007). The algorithm recommends a 4-day course of dexamethasone 0.15 mg/kg, six hourly, commencing with or before the initial dose of antibiotic is given to all patients with acute bacterial meningitis.
NURSING MANAGEMENT
Patients need to be closely monitored in the acute period. There are a number of secondary complications that can result in further deterioration of the neurological condition of the patient, e.g. hydrocephalus, cerebral oedema, cerebral infarction. The nurse needs to be vigilant for early signs of deterioration and to be aware of the specific management for the complications that can arise. It is therefore imperative that patients are nursed in an appropriate area where they can be closely monitored; the degree to which this will be required will depend on the clinical presentation of the individual patient. Some patients will require urgent transfer to intensive care if they have presented with severe shock and or coma. Other patients may be diagnosed early allowing for early treatment with antibiotics, and the clinical presentation is such that the patient does not at that time require monitoring in an ICU. However all patients are at risk of neurological deterioration and the nursing care discussed in the following section is relevant to all patients. The evidence for the nursing management of raised ICP has been presented in Chapter 7.
Airway and breathing
Immediate assessment and maintenance of a clear airway is the first priority. Patients who are deteriorating rapidly or who present with a Glasgow Coma Scale (GCS) of 8 or less will require intubation and respiratory support. Patients who are breathing spontaneously should be assessed regularly for an adequate depth and rate of breathing to allow for effective clearance of CO2. Patients who are drowsy are at risk of partial airway obstruction and hypoventilation which could lead to retention of CO2, which will increase ICP. Oxygen should be administered if necessary to maintain optimal oxygen saturations, i.e. >96%.
Patients who are able to follow commands should be encouraged to do regular deep breathing exercises to reduce the risk of respiratory complications.
Circulation
The patient should be regularly assessed for early signs of shock, i.e. rise in heart rate, prolonged capillary refill time, increase in respiratory rate, and reduced urine output. Hypotension is a late sign of shock. Blood pressure (BP) should be maintained to ensure a cerebral perfusion pressure (CPP) >60 mmHg (see Chapter 7).
Patients presenting with shock will require inotropic and vasopressor support to maintain CPP and perfusion to other vital organs. All patients should have continuous cardiac monitoring because of the risk of cardiac arrhythmias. Antipyretics should be administered regularly and cooling measures should be employed to reduce the temperature (see Chapter 7).
Neurology
In the acute stage the patient needs to be closely monitored for potential neurological deterioration. A minimum of half hourly neurological observations should be performed. All patients are at risk of developing a rise in ICP due to brain oedema and obstructive hydrocephalus. Signs and symptoms of raised ICP and management of ICP is presented in Chapter 7. Patients are also at risk of neurological deterioration due to cerebral infarction.
Seizures occur in approximately 17% of patients and are most likely to occur in the first 48 hours of hospitalisation (Wang et al., 2005). Appropriate safety measures should be in place to protect the patient in case a seizure should occur. If seizure activity occurs, rapid control is required to prevent ischaemic damage which can rapidly ensue due to the increased metabolic demands of the brain. Patients should be commenced on phenytoin and receive an initial loading dose of intravenous phenytoin 18 mg/kg following the first seizure. Intravenous lorazepam 4 mg should also be prescribed as required in case subsequent seizures occur.
Pain management
It is imperative to keep the patient comfortable and to reduce noxious stimuli. In the ward setting codeine based analgesia and paracetamol (acetaminophen) are administered for headache, whereas in the critical care setting the opioids fentanyl and morphine sulphate are commonly used. Opioid analgesics can compromise blood pressure so careful monitoring is required, particularly in patients who are haemodynamically unstable. Constipation is a common side-effect of opioid analgesics which should be managed before it becomes a problem by ensuring adequate hydration, a balanced diet and the use of prophylactic aperients. There is insufficient evidence for recommendations to be made about which analgesics are the most effective and have the least undesirable side-effects.
Fluid management
The aim is to maintain normovolaemia. Hypovolaemia can result in hypotension and a fall in cerebral perfusion pressure, which can predispose the brain to ischaemia; hypervolaemia can potentially exacerbate cerebral oedema. Frequent assessment of the patient’s hydration status and a strict fluid balance are necessary to inform decisions on fluid replacement. Patients with meningitis can develop syndrome of inappropriate production of antidiuretic hormone (SIADH). The patient will have dilutional hyponatramia and may require fluid restriction. However this must be done with the utmost caution so as not to compromise cerebral perfusion pressure.
Intravenous fluids containing dextrose should be avoided. Dextrose solutions will lower plasma osmolality; the hypo-osmolar state will cause water to move by osmosis across the BBB and will contribute further to cerebral oedema. Refer to Chapter 16 for further detail on the management of fluids and electrolytes and SIADH.
General nursing care
All patients with meningitis will either have raised ICP or are at risk of increased ICP, therefore general nursing care should aim to prevent and reduce possible elevations in the patient’s ICP (see Chapter 7).
TRANSMISSION
Community-acquired bacterial meningitis and meningococcal septicaemia are notifiable diseases. The consultant in communicable disease control or consultant in public health medicine should be notified promptly (Meningitis Research Trust, 2002). All close patient contacts are offered prophylactic antibiotics which will be coordinated by the public health team.
Patients with community acquired bacterial meningitis should be nursed in a side room for 24 hours; following this time there is no longer a risk of spread of meningococci. Health care workers who come into contact with patients with meningococcal meningitis do not require prophylactic antibiotics, however in the rare instance of the nose or mouth being splattered with droplets from the patient’s respiratory tract, e.g. during suctioning, prophylaxis should be considered. Appropriate precautions should be taken to prevent such contamination.
PROGNOSIS
Mortality and morbidity depends on the type of bacteria, the age of the patient and neurological condition at initial presentation. Streptococcus pneumoniae meningitis is associated with a mortality of 19%, N. meningitidis 13%, and H. influenzae 3% (Hankey and Wardlaw, 2008). Patients presenting with severe neurological impairments at presentation have very poor outcomes. Although associated with high mortality and morbidity the majority of patients who develop meningitis will go on to lead normal lives.
Viral meningitis
Viral meningitis is usually a very mild illness and the majority will make a full recovery and not require medical attention. A very small percentage of people with viral meningitis can make a slow recovery and have long term problems, such as persistent headaches, lethargy and memory impairments.
PHYSICAL, COGNITIVE AND PSYCHOSOCIAL IMPAIRMENTS FOLLOWING MENINGITIS
The risk of long term impairments is greatest in, but not confined to, those who experience neurological complications at the time of their acute illness.
Hearing loss
Cochlear damage can occur due to the direct effect of bacterial toxins which can lead to sensorineural deafness in approximately 20% of patients. Hearing loss can be mild to profound and can affect one or both ears. An early assessment of hearing should be performed to determine the degree of loss and to assess whether the patient is a candidate for cochlea implants. Alternative forms of communication such as lip reading and sign language may have to be learned (Donovan and Blewitt, 2009).
Patients should be given details of the Royal National Institute for Deaf People (RNID), which is a voluntary organisation that offers support and advice.
Cranial nerve palsies
One or more cranial nerve palsies occurs in 30% of patients, most commonly cranial nerves III, IV, VI, VII and VIII. See Chapter 13 for the specific care and management of cranial nerve impairments.
Epilepsy
Patients can continue to have seizures or go on to develop epilepsy following the acute period of the disease. It is important that patients and relatives are given appropriate information on antiepileptic drugs and what to expect during a seizure (refer to Chapter 30).
Cognitive impairments
The effect of memory loss can vary. Many people experience short-term memory loss, or find it hard to concentrate following meningitis. This can make everyday tasks very difficult and can cause problems when returning to work (The Meningitis Trust, 2002). Refer to Chapters 9 and 29 for strategies to manage memory loss.
Fatigue
Patients may experience fatigue for weeks or months following the disease. Management of fatigue is discussed in Chapter 28.
SUPPORT
The Meningitis Trust is a charity organisation in the UK that offers support, advice, counselling and financial support grants, and puts people in contact with others who have had similar experiences. It has a 24 hour nurse led helpline.
SUBACUTE MENINGITIS
Mycobacterium tuberculosis is a significant cause of meningitis in the UK. Approximately 2% of tuberculosis (TB) cases develop meningitis (Meningitis Trust, 2008). Unlike other types of meningitis it is rare for TB meningitis to present as an acute neurological emergency, rather there is a chronic presentation. Most commonly the patient has a history of weight loss, fever, night sweats and malaise. Anti-TB drugs are given for six to nine months depending on the severity of the disease and the response to treatment. Table 24.1 lists the initial anti-TB drugs and their adverse effects, which are numerous. Patient education and support is essential to optimise adherence. Liver function tests are performed at regular intervals; isoniazid is stopped if symptoms of hepatitis are present. Streptomycin can be used instead of rifampicin, and ethambutol can be substituted for pyrazinamide if adverse effects become a problem (Hankey and Wardlaw, 2008). Dexamethasone 12 mg is given for three weeks and then tapered for a further three weeks. Neurological impairments persist in 20–30% (Hankey and Wardlaw, 2008) and are similar to those for other types of bacterial meningitis.
Table 24.1 Initial anti-TB treatment.
| Drug | Dose | Adverse effects |
| Rifampicin | 600 mg OD |
|
| Pyrazinamide | 30–50 mg/kg OD |
|
| Isoniazid | 5 mg/kg OD |
|
| Pyridoxine (given to prevent peripheral neuropathy associated with the use of isoniazid) | 20–50 mg OD |
Source: Hankey and Wardlaw, 2008; Joint Formulary Committee, 2009.
ENCEPHALITIS
Encephalitis is inflammation of the brain tissue. It can occur at any age, in any part of the world. It is caused by either an infection (usually viral, but can be bacterial, fungal or parasitic) or by autoimmune disease. The initial stage of the illness commonly manifests as serious, acute and potentially life-threatening. Many patients are left with an acquired brain injury, although the degree and severity of permanent brain injury varies among those affected (Easton et al., 2006).
EPIDEMIOLOGY AND AETIOLOGY
Very few epidemiological studies of encephalitis exist and the disorder is probably under-reported. Beghi et al. (1984) reported the US annual incidence as 7.4 people per 100,000 and, more recently, Khetsuriani et al. (2002) reported 7.3 hospitalisations per 100,000 population. There are no statistics for the UK, but based on the US figures it can be estimated that the incidence in the UK is about 4,000 cases per annum.
The most commonly identified infective cause in the UK is herpes simplex. Other commonly identified causes are herpes zoster, Epstein–Barr virus, mumps, measles and enteroviruses.
There are three broad types of encephalitis: acute infective encephalitis, post-infectious encephalitis (also known as acute disseminated encephalomyelitis or ADEM), which is an autoimmune process following infection elsewhere in the body, and finally auto-immune responses to other conditions in the body such as tumour or when antibodies block sites on nerve cells in the brain, preventing them from functioning normally. Examples include voltage-gated potassium channel antibody encephalitis (VGKCaE) or anti-N-methyl-D aspartate receptor encephalitis (Anti-NMDAR encephalitis). The latter of these three types of encephalitis is of some significance since with early diagnosis and treatment, patients can recover well from some auto-immune encephalitides.
PATHOPHYSIOLOGY
Clinical manifestations are caused by cell dysfunction from direct infective invasion and associated inflammatory change (Hankey and Wardlaw, 2008) or by a secondary immune response to infection or immunisation. Inflammation may be widespread throughout the brain, often accompanied by inflammation of the meninges (meningo-encephalitis), or it may be localised, for example to the limbic system or the brain stem. Cerebral blood vessels become surrounded by lymphocytes and plasma cells, known as perivascular cuffing, which is characteristic of inflammatory processes.
Some viruses have a predilection for particular parts of the brain. Herpes simplex virus causes inflammation and haemorrhagic necrosis in the frontal and temporal lobes. Rabies virus tends to involve the medial temporal lobes, and varicella-zoster virus involves the cerebellum.
Infections are most commonly transmitted to the brain via the bloodstream (haematogenous spread). The infectious agent – often a virus introduced into the body by an insect bite – is present in the blood (viraemia) and crosses the blood–brain barrier into the brain. Infected neurones may rupture and subsequently the immune response causes inflammation and cerebral oedema, leading to raised intracranial pressure.
Some infections, such as rabies and herpes encephalitis, travel directly along neurones into the brain and some, such as herpes simplex and varicella zoster, may establish a persistent presence in sensory ganglia, which may lead to disease at a later stage. It has been known since the 1920s that the herpes virus can travel from its first site of entry into the body to the sensory ganglion cells and then on into the central nervous system (Goodpasture and Teague, 1923).
The most commonly identified non-infectious encephalitis is acute disseminated encephalomyelitis (ADEM) (Garg, 2006). In ADEM, there is widespread demyelination in the white matter of the brain and spinal cord. In developed countries, ADEM is now most often seen following mild upper respiratory infections. In developing countries other infections, such as measles, rubella and varicella, are more common causes of ADEM. Acute haemorrhagic leucoencephalitis (AHLE) is a more severe variant of ADEM and is often fatal (Garg, 2006). There is a characteristic necrotising vasculitis, often with areas of haemorrhage around blood vessels.
CLINICAL SIGNS AND SYMPTOMS
Onset is commonly insidious; patients often have a several day history of malaise, myalgia and headache. 90% of patients will have a fever on presentation (Howard and Manji, 2009). Seizures frequently occur with acute infective encephalitis. Patients can also present with nausea, vomiting and signs of meningeal irritation (see: Clinical signs and symptoms). Reduced level of consciousness and raised ICP may also be present. Behavioural and speech disturbances may also be present.
DIAGNOSIS
The symptoms of encephalitis are shared with other illnesses, so differential diagnosis can be difficult (Whitley and Gnann, 2002). The presence of focal seizures and focal neurological signs can differentiate encephalitis from other encephalopathology (Chaudhuri and Kennedy, 2002). CT scanning is usually performed to rule out mass lesions and other pathology as well as to evaluate cerebral oedema when MRI is not available (Steiner et al., 2005; Solomon et al., 2007). CT scanning may also be used to rule out any mass effects before conducting a lumbar puncture. Where it is safe to do so, a lumbar puncture is an essential tool in the diagnosis and treatment of encephalitis and may be performed to assess CSF pressure and to obtain samples for infection screening. The diagnosis can be confirmed by the polymerase chain reaction (PCR) test for infections within the CSF (Chaudhuri and Kennedy, 2002; Solomon et al., 2007). MRI may be able to detect other abnormalities early in the disease (Chaudhuri and Kennedy, 2002; Steiner et al., 2005).
A good algorithm regarding the diagnosis and treatment of encephalitis in the immunocompetent patient has been developed by the Liverpool Brain Infections Group (Solomon et al., 2007).
MEDICAL MANAGEMENT
Viral encephalitis is a medical emergency and, if suspected, treatment with anti-viral agents should be initiated without delay (Solomon et al., 2007). The earlier that treatment is commenced, the less the risk of long-term complications. There is no specific therapy for most forms of viral encephalitis (Chaudhuri and Kennedy, 2002), with the exception of acyclovir for herpes simplex encephalitis and varicella-zoster encephalitis, however other anti-viral agents continue to be evaluated (Steiner et al., 2005). Younger patients below 30 years of age (Whitley and Gnann, 2002) and those in whom the duration of encephalitis was two days or less when acyclovir was started, have been shown to have better outcomes (Raschilas et al., 2002) , although even with treatment the mortality from this disease remains high at 20–30% (Kennedy and Chaudhuri, 2002).
Acyclovir is administered intravenously three times daily (in the relevant dosage for the patient’s bodyweight) for 14 days in immunocompetent patients, and for up to 21 days where the PCR remains positive, or the patient continues to be febrile (Solomon et al., 2007) to prevent relapse. It may be discontinued if an alternative diagnosis is identified. Acyclovir selectively inhibits viral DNA in infected cells, thereby preventing viral reproduction and spread, while healthy cells are unaffected (Kennedy and Chaudhuri, 2002). Patients with herpes simplex encephalitis who are treated with acyclovir early, before they become comatose, have reduced morbidity and mortality (Steiner et al., 2005). Side-effects include headache, nausea and vomiting and diarrhoea and more rarely hallucinations and liver failure.
High dose steroids have also been tried, but there is little evidence of effectiveness (Steiner et al., 2005), although dexamethasone may be used for cerebral oedema. Symptomatic relief should also be initiated, such as intravenous phenytoin to control seizure activity, and anti-pyretics to reduce fever.
Secondary neurological complications include cerebral infarction, cerebral venous thrombosis, SIADH (see Chapter 16), and aspiration pneumonia (Steiner et al., 2005).
NURSING MANAGEMENT
The acute nursing management is the same as for meningitis with the exception of the need for isolation. It is not uncommon for patients to be agitated and aggressive; strategies to manage these behaviours are presented in Chapter 10.
PROGNOSIS
Mortality resulting from infection by the herpes virus (the most common identified cause of viral encephalitis) is 20–30% with treatment. If encephalitis is left untreated, the mortality rate is about 70% (Schott, 2006).
PHYSICAL, COGNITIVE AND PSYCHOSOCIAL IMPAIRMENTS FOLLOWING ENCEPHALITIS
Encephalitis can have lasting repercussions for a person’s day to day functioning. In a large survey, 69% of adult respondents reported that their illness had left them unable to return to their premorbid lifestyle, and 20% had suffered a breakdown in marriage following the illness (Dowell et al., 2000). The effects of encephalitis upon an individual’s quality of life and interpersonal relationships clearly persist beyond the acute period of neurological infection (Easton et al., 2006).
One of the primary goals of rehabilitation is to facilitate the patient’s return to living, working and socialising independently (Rössler and Haker, 2003; Wilson, 2003). Nurses need to consider not only to the neuro-anatomical foundations and neurological effects of an illness, but also the psycho-social aspects, incorporating cognitive, emotional, behavioural and social factors (Williams and Evans, 2003; Wilson, 2003). Cognitive impairment can negatively impact on recovery.
Cognitive impairment
The most severe deficits to cognition are usually associated with herpes simplex type-1 encephalitis. These can present with pervasive amnesia covering new material and/or existing memories (Hokkanen and Launes, 2000; Pewter et al., 2007), communication problems such as incorrectly naming items (Okuda et al., 2001) and impairment of executive functions such as attention and planning ability (Pewter et al., 2007).
While, on the whole, non-herpetic encephalitis does not result in the same degree of cognitive impairment, amnesic and other cognitive deficiencies may occur, highlighting the importance of assessing patients on a case-by-case basis (Hokkanen and Launes, 2000; Pewter et al., 2007). Hokkanen and Launes (2000) also note the occurrence of behavioural indications of executive impairment, including: impulsive, disinhibited actions, rigid behaviour, and lacking in initiative. Situationally inappropriate actions and speech have also been reported (Evans, 2003; Godefroy, 2003) even in the absence of evidence on formal testing. Recently, subtle deficits in tasks requiring executive function have been found across a wide range of patients with various aetiologies of encephalitis (Pewter et al., 2007). These problems may, therefore, be widespread and may contribute to the behavioural difficulties and fatigue experienced by encephalitis patients.
Depression and anxiety
In addition to problems with cognition, encephalitis can result in lasting depression, anxiety and psychiatric illness (Pewter et al., 2007). Difficulties with emotional adjustment are common and can be pervasive and severe regardless of the severity of cognitive and neuroanatomical damage (Kreutzer et al., 2001). The presence or absence of insight into one’s condition is thought to be an important mediator between cognitive impairment and psychological distress (Fleminger et al., 2003). While awareness is often disturbed early in the course of recovery, improving insight during the months and years following injury can lead to reactive depression as the patients find themselves aware of their acquired limitations (Godfrey et al., 1993). Since disturbance of insight is more resilient in more severely brain-injured cases, the presence of greater cognitive and psychosocial difficulties in this population can produce less subsequent depression, as patients may be less aware of the change in their abilities. Emotional dysfunction may, therefore, be equally or more problematic in patients with seemingly milder neurological injury.
Despite the role of emerging insight in triggering depression, accurate self-appraisal may be beneficial to the long-term adjustment, as greater self-awareness may produce greater motivation and ability to compensate for acquired difficulties and patients may find themselves less frustrated by attempting activities which are beyond their current capability (Ownsworth and Fleming, 2005). This is supported in one study of post-acute encephalitis patients which found that realistic self-appraisal was associated with a lesser degree of depression (Pewter et al., 2007).
Socialising and employment
Little is currently known about the impact of encephalitis upon socialisation. However, individuals with a brain injury do tend to receive fewer visitors and to socialise less than the normal population, relying upon the immediate family for social contact (Elsass and Kinsella, 1987; Marsh et al., 1990). This reliance upon the family can place additional strain upon relationships as the parents (Hooper et al., 2007) and carers (Pewter, 2007) of encephalitic patients frequently report emotional distress relating to the neurobehavioural symptoms displayed by their relative. Subsequently, carers of a brain injured person report increased instances of alcoholism, tranquiliser usage, attendance of counselling for mental health problems, marriage breakdown, anxiety, depression and distress (Hall et al., 1994; Kreutzer et al., 1994). Nurses must be vigilant for distress among family members and offer support. The Encephalitis Society (2003; 2010) also provides support for patients, their families and carers and nurses should ensure that their contact details are passed on (www.encephalitis.info).
The workplace is another avenue for social contact. Between 26 and 70% of encephalitic patients successfully return to work, depending upon the aetiology and severity of their encephalitis (Hokkanen and Launes, 1997; Kaplan and Bain, 1999). While cognitive problems are in themselves a barrier to employment (Dikmen et al., 1993), Andrewes and Gielewski (1999) report the case of one patient who was unable to remember which of her work colleagues had acted in a friendly manner towards her, making it difficult to maintain amicable relationships with colleagues.
Clinical neuropsychology/neuropsychiatry involvement
Given the breadth of socio-emotional problems faced by survivors of brain injury, the patient must be referred for clinical neuropsychology and/or neuropsychiatry assessment. Nurses are ideally placed to ensure timely and appropriate referrals. As noted above, anxiety and depression are very common and there is a corresponding three-fold increase in the risk of suicide (Fleminger et al., 2003). There is some provision for the treatment and management of brain injury and nurses need to ensure that such services are made clearly available for encephalitis patients (Easton et al., 2006). For example, biological and bio-psycho-social treatment for depression and suicidal ideation are available through clinical psychology services (Fleminger et al., 2003). In addition, anxiety-related disorders such as obsessive-compulsive behaviour can be distressing to post-encephalitis patients (Pewter et al., 2007), but evidence from some cases has shown that cognitive behaviour therapy can help (Williams, 2003).
Fatigue
Fatigue can be a considerable problem following encephalitis, as compensating for any residual cognitive deficits can be stressful and tiring even when such compensation is successful enough to allow outwardly normal autonomous functioning (Greve et al., 2002). Management of fatigue is discussed in Chapter 28.
Epilepsy and seizures
Epilepsy can be a significant problem for people after encephalitis, with nearly a quarter of people affected by encephalitis as an adult going on to experience seizures, and nearly half of all those affected as a child (Dowell et al., 2000). See Chapter 30 for the management of seizures.
Headaches and bodily pain
Changes in sensation, headaches and pain in other parts of the body can last for several weeks after the acute illness, and sometimes may continue for some time after the acute phase. These may be made worse by lack of rest, having to concentrate hard, and/or bright lights. Dizziness also may occur, especially with sudden or rapid movement and may be accompanied by feeling nauseated. While stress and tension are usually the main causes, a doctor should always check persistent headaches or pain and referral to a pain clinic may be necessary where these problems persist (The Encephalitis Society, 2010).
Sensory changes
Vision, hearing, taste, smell, temperature and touch can all be affected by encephalitis. Problems can range from the complete loss of a sense to variations in sensitivity from one day to the next.
Hearing problems can occur for a number of reasons. Tinnitus is experienced as noise, commonly like a buzzing, hissing or ringing in the ears. Auditory agnosia is impaired recognition of non-verbal sounds and noises, but intact language function. In some cases the person can be extremely sensitive to certain noises, pitches, or where there is more than one sound at a time. They may be unable to tolerate many environments we take for granted (for example shopping centres and pubs).
Encephalitis: patient perspective
It locks you away
inside your mind
inside your head
it keeps you alone
and different
Deep down you know
what the difference is
who you used to be
the person you once were
But who are you now?
Try and explain it to others
can they really understand
Try saying “I feel different”
Folks politely ask me why?
Its simple,
my mind is like treacle
(the extra sticky kind)
that pulls out all your fillings
and causes your teeth to grind
My head is like a vacuum. …
of the cleaning type
that sucks up bits and pieces
clears away in one full swipe.
My memory is shot to pieces
my arms and legs are weak
my balance is non existent
held up by two left feet.
There’s my vision too
my eyes – mere shadows
of their former selves
Two friends who find it hard to
work
although they can with help.
Some mornings I find it hard to
wake
My brain’s been left behind
It’s vanished, gone the night before
Looking for things I cannot find.
I feel like something’s got me
Something weird form outer space.
Am I a “Stepford wife”, a “zombie”?
Am I part of the Human Race?
It doesn’t feel like it.
Do they tell you about the head pain,
The pressure building up,
The depression and the mood swings,
Desperation fills my cup.
My tendency to drop things
through my fingers light and weak
How many pairs of trousers torn
from falling off my feet.
Its changed my personality
every ailment caused by you
And so the list continues
my life revolves around –
trying to get over this
dreadful illness.
Encephalitis,
it changes life,
it changes you.
Source: The Encephalitis Society. Reproduced by kind permission of the Encephalitis Society.
FURTHER INFORMATION
Further information for patients and professionals can be obtained from the encephalitis society (www.encephalitis.info).
CEREBRAL ABSCESS
AETIOLOGY AND EPIDEMIOLOGY
An abscess is a localised collection of pus within the brain parenchyma. In the UK the prevalence is 2–3 cases per million (Fitzpatrick and Gan, 1999). A cerebral abscess develops as a result of spread of infection from adjacent structures, i.e. the middle ear or paranasal sinuses; following post-operative infections or penetrating trauma; or haematogenous spread of infection from teeth, pulmonary abscess or bacterial endocarditis. The most common causative organisms are Staphylococcus aureus (following trauma), Streptococcus pneumoniae and Streptococcus milleri. More than one organism can be isolated particularly when dental infection is the cause.
PATHOPHYSIOLOGY
The initial stage of abscess formation is focal inflammation and oedema of the periphery of the brain (cerebritis).The cerebritis evolves into a cerebral abscess which has a central core of necrotic tissue and pus forms in the abscess cavity. A collagen capsule surrounds the abscess.
CLINICAL SIGNS AND SYMPTOMS
Headache, fever, reduced consciousness, seizures and focal neurological signs are the most common presenting signs and symptoms.
DIAGNOSIS AND MEDICAL MANAGEMENT
Diagnosis can be confirmed with a CT with contrast, or by MRI. The original source for the infection is usually apparent from the medical history, e.g. long standing untreated dental infection. Small abscesses can be treated with intravenous antibiotics for the specific causative organism (Howard and Manji, 2009). Antibiotic therapy is usually required for several weeks. Large abscesses may require surgery in the form of craniotomy and excision or stereotactic guided aspiration to reduce ICP. In some cases the latter is performed to determine the causative organism.
NURSING MANAGEMENT
The acute nursing management is the same as for meningitis, with the exception of the need for isolation. See Chapter 20 for post-operative nursing management.
PROGNOSIS
Prognosis is poor in patients who have impaired consciousness and neurological impairments on admission, but is excellent for those who are fully conscious (Howard and Manji, 2009).
NEUROLOGICAL COMPLICATIONS OF HUMAN IMMUNODEFICIENCY VIRUS (HIV)
EPIDEMIOLOGY OF HIV
The acquired immunodeficiency syndrome (AIDS) was first recognised in 1981 and is caused by the human immunodeficiency virus (HIV-1). HIV-2 causes a similar illness to HIV-1 but is less aggressive and is restricted mainly to Western Africa. The viruses originated from the closely related African primate simian immunodeficiency viruses, and sequence analysis has led to the estimate that HIV-1 was introduced into humans in the early 1930s (Holmes, 2001).
AIDS has grown to be the second leading cause of disease burden worldwide. It is now recognised that the immune deficiency is a consequence of continuous high-level HIV replication, leading to virus and immune-mediated destruction of the key immune effector cell, the CD4 lymphocyte. HIV affects 33.2 million people in the world with 2.5 million new cases and 2.1 million deaths as estimated by the World Health Organisation in 2007, indicating a levelling off of the global epidemic. Sub-Saharan Africa has the greatest burden of disease.
In the UK in 2006, 7093 new cases occurred, with an estimated overall prevalence of 73,000 (Health Protection Agency, 2007); approximately 21,600 of these are undiagnosed as calculated using population estimates and anonymous linked testing. The epidemic in many industrialised nations is changing, with heterosexual transmission becoming the dominant route and racial and ethnic minorities representing an increasing fraction. Worldwide, the major route of transmission (> 75%) is heterosexual; 5–10% of new HIV infections are in children and more than 90% of these are infected during pregnancy, birth or breastfeeding (WHO, 2007). The incidence in injecting drug users varies widely from country to country. It is relatively low in the UK being <1% in most areas, although in other areas of the world (e.g. Eastern Europe, Vietnam, North-East India and China) it accounts for the majority of infections.
HIV-2 differs from HIV-1 in that patients have lower viral loads, slower CD4 decline, lower rates of vertical transmission, and slower progression to AIDS. The economic and demographic impact of HIV infection in developing countries is profound as it affects the most economically productive and fertile ages and is also eroding the health and economic advances made in the last few decades. Access to antiretroviral (ARV) therapy for patients with HIV-related illness in resource-poor nations has improved significantly over the last few years with over 2 million receiving treatment, which represents approximately 28% of those estimated to require treatment.
Modes of transmission
HIV infection occurs by transmission of the virus to an uninfected individual by exposure to infected fluids. This can be by contact with blood, bodily fluids, sexual contact, and through breast milk. Likelihood of infection is dependent on the integrity of the exposed site, the type and volume of body fluid, and the viral load.
PATHOPHYSIOLOGY
HIV is a single-stranded RNA retrovirus from the lentivirus family. Following mucosal exposure, HIV is transported to the lymph nodes via dendritic, CD4 or Langerhans cells, where infection becomes established. Free or cell-associated virus is then disseminated widely through the blood with seeding of ‘sanctuary sites’, such as the CNS and testes, as well as latent CD4 cell reservoirs. With time, there is gradual attrition of the CD4 cell population resulting in increasing impairment of cell-mediated immunity with consequent susceptibility to opportunistic infections and certain cancers (Palella et al., 2003). It has been calculated that each day more than 1010 virions are produced and 109 CD4 cells destroyed.
As CD4 cells are pivotal in orchestrating the immune response, any depletion in numbers renders the body susceptible to opportunistic infections (e.g. mycobacterium tuberculosis) and oncogenic virus-related tumours. The reduction in the number of CD4 cells circulating in peripheral blood is tightly correlated with the amount of plasma viral load. Both are monitored closely in patients and are used as measures of disease progression. The further a CD4 cell count falls below 200 cells/mm3 the more likely the patient is to develop an opportunistic infection.
CLINICAL SIGNS AND SYMPTOMS
As a neurotropic virus, HIV causes complex disease and usually infects the central nervous system early in infection (Kumar, 2007). Therefore neurological disease is a common feature of HIV infection and may present as part of an acute HIV seroconversion, or as a chronic process related to immunosuppression, or as a direct result of chronic viral infection.
Acute HIV infection/seroconversion
HIV seroconversion describes the process of conversion from HIV antibody negative to antibody positive. Most patients with HIV are diagnosed in the latent rather than acute stage of disease hence a substantial proportion of people are asymptomatic or mildly symptomatic at acute infection. As well as a transient flu like illness, patients may report a variety of symptoms including fever, rash, generalised lymphadenopathy, pharyngitis, diarrhoea, myalgia, arthralgia or headache. As a result of a rapid drop in CD4 T-lymphocyte cells during this phase of infection patients may be at risk of developing opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP), although this is rare (Vento et al., 1993).
Potential neurological manifestations of acute HIV infection include aseptic meningitis and rarely, a self limiting encephalopathy, Guillain–Barré syndrome, transverse myelitis, facial palsy, polyradiculitis and peripheral neuropathy.
Cryptococcal meningitis
The yeast Cryptococcus neoformans is the most common cause of meningitis associated with late stage HIV (CD4 <50 cells/mm3). Many of the typical signs and symptoms of meningitis are absent. Most patients present with several weeks history of headache, fever and malaise. Focal neurology and seizures are rare but mild confusion is often a feature. Death occurs in 5–12% of patients within the first 2 weeks of diagnosis (Robinson et al., 1999).
Toxoplasmosis
Toxoplasma gondii is a protozoan parasite carried by domestic and non-domestic animals with the final host being the cat. Humans become exposed through contact with the faeces of an infected cat or through eating undercooked contaminated meat. In the immunocompetent individual toxoplasmosis is rarely symptomatic (except during pregnancy where issues of miscarriage and foetal abnormalities arise). However in those infected with HIV the risk of developing toxoplasma-related pathology is high once the CD4 cell count falls below 100 cells/mm3. At this stage the patient is at risk of reactivating disease or developing acute infection as a result of primary exposure to the parasite. In the presence of HIV infection there is a > 30% risk of a previously infected individual reactivating their disease.
Although it may manifest itself in other organs, toxoplasmosis most commonly presents with encephalitis. It may cause widespread microscopic lesions and brain abscesses. Patients give a short history of headache, fever and drowsiness, which is rapidly followed with confusion, seizures and focal neurology. The areas of the brain most commonly infected include the parietal and frontal lobes, thalamus, basal ganglia and corticomedullary junction. Lesions are difficult to differentiate from CNS lymphoma.
Primary CNS lymphoma (PCNSL)
This haematological malignancy (a tumour of lymphocytes or lymphoblasts confined to the CNS) normally complicates late stage HIV when the CD4 cell count has fallen below 50 cell/mm3. It occurs in approximately 5% of AIDS patients.
There are usually multifocal mass deposits in the brain. At the initial presentation lesions of PCNSL are often difficult to differentiate from those of toxoplasmosis due to similarity in clinical signs and symptoms, as well as presentation at the same advanced stage of HIV disease. However the duration of illness tends to be less rapid and may progress over weeks to months. Patients may present with headache, personality change, seizures, confusion or dulling of intellect and focal neurological signs correlating to the affected region within the brain.
Progressive multifocal leucoencephalopathy (PMFL)
This is a rapidly progressing demyelinating disease of the central nervous system caused by JC virus, which is usually fatal. It is normally associated with advanced stage HIV where the CD4 count is <50 cells/mm3, however it has been described in patients with CD4 higher than 200 cells/mm3. It is thought to be due to reactivation of latent JC virus, which the majority of the population are exposed to in childhood or early adulthood when an asymptomatic primary infection occurs. Patients present with focal deficits in 80% of cases, visual field defects and ataxia; seizures are not usually a feature.
Cytomegalovirus (CMV) encephalitis
CMV encephalitis is a rare presentation of CMV disease, which more commonly presents with retinopathy or colitis. Central nervous system disease presents with headache, neck stiffness and confusion.
Central nervous system tuberculosis
Co-infection with HIV and Mycobacterium tuberculosis is common. CNS tuberculosis includes tuberculous meningitis, tuberculoma and spinal TB. In HIV positive patients with TB, pulmonary disease is more prevalent in those with a relatively preserved immune system (CD4>200 cells/mm3); however with more advanced disease extra-pulmonary infection, including tuberculous meningitis, becomes more common. In both the HIV and non-HIV setting the presentation of TB meningitis is similar and it carries a high degree of mortality and morbidity. However mortality is significantly greater in the HIV-infected group whereas morbidity is the same. Patients typically present with a prolonged insidious illness including fever, headache, meningism, focal CNS signs (see: Subacute meningitis). Patients are often slow to respond to therapy and may clinically and neurologically deteriorate before they begin to improve.
Other
A predominantly distal sensory neuropathy affecting the lower limbs is found in 30% of HIV-infected patients and is associated with lower CD4 counts (<200 cells/mm3), high viral loads and older age. It results from axonal degeneration especially in unmyelinated nerve fibres. Hyperaesthesia, paraesthesia and pain or burning in the feet are common features. Diminished pinprick, light touch and vibration sense in association with loss of ankle reflexes is found. Certain anti-retroviral drugs are implicated in this pathology especially didanosine (ddI), stavudine (d4T), hydroxyurea and zalcitabine (ddC). With advances in HIV research newer drugs have been developed that are less likely to cause peripheral neuropathy and therefore the drugs implicated with this condition are now avoided where other options are available.
DIAGNOSIS AND INVESTIGATIONS
Diagnosis of HIV-related pathologies is often complicated and the time from presentation to diagnosis may be weeks to months. In all cases an accurate and detailed clinical history and examination is required in combination with laboratory investigations. When the pathology involves the central nervous system, neuro-imaging is essential with MRI scans providing more detailed information to aid the diagnosis. CT scan is often used as a screening tool, outside of normal working hours, to rule out acute pathology that warrants urgent action as well as helping the clinician to decide if it is safe to perform a lumbar puncture. At times electrophysiological studies may be helpful, such as EEG with suspected encephalopathy or nerve conduction studies in the presence of a peripheral neuropathy.
All patients with HIV-related central neurological disease require a lumbar puncture unless contraindicated. This allows assessment of intracranial pressure and cerebrospinal fluid protein, glucose (compared to blood glucose), cell count, and specific stains, typically Gram, Ziehl–Neelsen (to diagnose tuberculosis) and India ink (to diagnose cryptococcal infection). Standard and extended (TB and fungal) culture should be performed as well as qualitative molecular (PCR) tests for TB, toxoplasma, CMV, JC virus, EBV, herpes simplex and varicella zoster viruses. Quantitative tests may be indicated for HIV (dementia/encephalopathy), JC virus (PMFL), and EBV (PCNSL).
On occasions despite extensive investigation the diagnosis remains unclear. At this stage neurosurgical opinion should be sought concerning a brain biopsy as tissue histology and microbial detection often help and may be the only method of coming to a conclusive diagnosis.
MEDICAL MANAGEMENT AND DRUGS
Antiretroviral treatment
The naïve patient
The decision to start therapy is a major one. It is dependent upon the symptom status of the patient, the CD4 count (and/or CD4%) and how quickly the level falls, the presence of co-morbidities, and the wishes of the patient. The risk of HIV-related disease and treatment-related toxicity increases as the CD4 falls and the likelihood of immunological recovery decreases. Nevertheless, successive surveys have demonstrated that up to one-third of patients do not present with their HIV until they are at an advanced stage when morbidity and mortality are not insignificant. Current practice is to recommend commencing treatment when the CD4 count falls below 350 cells/mm3, above which the patient is rarely symptomatic (Gazzard et al., 2008).
There are three major classes of drugs: nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). A potent combination (highly active antiretroviral therapy; HAART) should always be used and consists of three or more drugs: two NRTIs and either an NNRTI or a ritonavir-boosted PI. When starting treatment many factors need to be considered including: the potential drug interactions (e.g. anti-tuberculosis therapy), the presence of viral resistance, and patient lifestyle and wishes (e.g. a preference for once daily). Commencing antiretroviral therapy is not an emergency and there is always time to decide with the patient their optimum regimen thereby maximising adherence to the combination. All patients should have a viral resistance test performed prior to commencing therapy as there is a 5–10% incidence of primary viral resistance.
The treatment-experienced patient
A change in antiretroviral therapy may be necessary because of drug side-effects (early or late), difficulties in adherence, or virological failure. In a patient with a previously undetectable virus load (VL) (virus load is the measure of severity of viral infection) virus rebound is usually the first evidence of treatment failure.
With increasing time on a failing regimen, the VL rises towards baseline levels, resistance mounts, the CD4 count falls and clinical progression occurs. In essence, most early failures are related to adherence difficulties and most late failures are a result of virological resistance.
A new combination is decided upon based mainly on the result of a resistance test and prior drug exposure. Recent pharmacological developments have led to the introduction of two major new drug classes: entry inhibitors (fusion and chemokine receptor), and integrase inhibitors. These are of major advantage in treatment experienced patients who have extensive resistance to the standard therapies. These new drugs offer the patient treatments that are potent against their virus and can help them attain an undetectable viral load once again.
Cryptococcal meningitis
In addition to the management outlined under Acute bacterial meningitis/Medical management and treatment there are three phases in the management of cryptococcal meningitis: induction, maintenance, and secondary prophylaxis.
First-line induction treatment for cryptococcal meningitis is amphotericin B (0.7–1 mg/kg/day) with flucytosine (100 mg/kg/day), although the advantage of additional flucytosine is debatable. Standard amphotericin B should be used but this may be associated with renal toxicity, in which case liposomal amphotericin should be used. In patients with good prognostic factors, fluconazole (400 mg/day) is an alternative; itraconazole (400 mg/day) is less active than fluconazole and should only be used if other agents are contraindicated (Pukkila-Worley and Mylonakis, 2008).
Maintenance therapy and prophylaxis follows two weeks of induction therapy or CSF sterility. The patient should be switched to maintenance therapy with oral fluconazole 400 mg daily which is continued for a further six to eight weeks after which the dose is dropped to 200 mg daily. This represents secondary prophylaxis and should be continued until the CD4 count is >200 cells/mm3 and there is HIV viral undetectability.
All patients with cryptococcal disease should receive HAART and this should be commenced when it is safe to do so, usually at around two weeks when the patient is being switched from induction to maintenance therapy. When HAART is commenced immune responses are restored, an adverse consequence of this can be preexisting opportunistic infections clinically deteriorate which is referred to as immune reconstitution disease (IRS). There is a 10–20% occurrence of IRS which most commonly presents as culture-negative ‘relapse’ of meningitis.
Toxoplasmosis
Despite the characteristic imaging, it is often impossible to distinguish toxoplasma encephalitis from PCNSL with confidence. However, the response to a trial of anti-toxoplasma therapy is usually diagnostic, with clinical improvement occurring within the first week and significant reduction in the size of their lesions on imaging in the second week in over 90% of patients with toxoplasmosis. Treatment is divided into three phases: induction, maintenance, and prophylaxis. In addition, awareness of raised intracranial pressure from mass effect and the timing of HAART and complications of immune restoration are important considerations.
First line treatment is pyrimethamine (initial daily loading dose of 100–200 mg for two days followed by 50–100 mg daily) and sulphadiazine (1 to 2g qds) given for six weeks: pyrimethamine is given with folinic acid 15 mg daily. Dexamethasone (4 mg qds) should be given if there is significant mass effect (Montoya and Liesenfeld, 2004), however this may make it harder to differentiate between toxoplasmosis and PCNSL as the latter will also respond to steroids. The steroid dose should be tapered with clinical improvement over the ensuing two to four weeks.
Following successful induction, maintenance with pyrimethamine and either sulphadiazine or clindamycin should be continued at lower doses until the patient is successfully established on HAART with a CD4 count >200 cells/mm3. Co-trimoxazole 960 mg is an alternative, and is the preferred primary prophylactic in patients seropositive for toxoplasma. Failure to respond clinically and radiologically to therapy indicates the need for an urgent brain biopsy. All patients with cerebral toxoplasmosis should receive HAART and this is usually commenced around two weeks when the patient is being switched from induction to maintenance therapy. There is a small risk of immune reconstitution disease (IRS) which most commonly presents as paradoxical enlargement of the toxoplasma mass lesions.
Primary CNS lymphoma
Treatment is usually palliative with dexamethasone and symptomatic relief. Occasional responses to HAART have been reported but chemotherapy (methotrexate is the treatment of choice) and radiotherapy rarely produce much prolongation of survival which is usually 3–6 months.
Progressive multifocal leucoencephalopathy (PMFL)
There remains no specific treatment for PMFL outside of commencing or optimising antiretroviral drug treatment. HAART improves prognosis if commenced or optimised at time of diagnosis; however, mortality rate remains at 50% by one year. Some patients enter true remission of disease with stabilisation of neurological morbidity and the development of atrophy and gliosis on MRI.
Cytomegalovirus (CMV) encephalitis
Treatment for CMV is split into two phases: induction for two weeks followed by maintenance until there is sufficient immunological recovery (usually >200 cells/mm3), loss of CMV viraemia in blood and CSF, and clinical and neuroimaging features have regressed or stabilised. Therapy can then be discontinued. Ganciclovir IV is recommended for the induction therapy of CMV encephalitis and/or retinitis (Kedhar and Jabs, 2007). Foscarnet or cidofovir are two alternative second line agents though they have potential toxicities. Valganciclovir may be preferred if patient circumstances make IV administration inappropriate and it is the preferred choice for maintenance therapy after 2 weeks. Prophylaxis is not indicated.
TB meningitis and tuberculoma
As immune function falls, the likelihood of non-pulmonary tuberculosis, including both focal cerebral and meningeal disease, increases significantly. Therapy is split into two phases: induction and maintenance. In addition, awareness of the possibility of TB mass lesions (tuberculomas) developing or enlarging and the timing of HAART and complications of immune restoration are important considerations.
Induction therapy for known or presumptive fully sensitive mycobacterium tuberculosis is standard quadruple therapy, consisting of rifampicin, isoniazid, ethambutol, and pyrazinamide given for two months (with supplemental pyridoxine to prevent isoniazid neuro-toxicity) (see: Subacute meningitis). Induction is followed by a 10 month maintenance phase with rifampicin and isoniazid. Fixed-dose combinations of drugs simplify the administration of therapy, improve adherence, and facilitate directly observed therapy (DOT) on a daily or three times weekly basis. Corticosteroids should be used in a decremental regimen as described for HIV-negative patients (Thwaites et al., 2004). Choice of HAART is complicated due to drug interactions. IRS occurs in up to 20% of patients. This usually occurs 4–8 weeks after initiation of TB-therapy and is most common in those with a nadir CD4 <50 cells/mm3 and a brisk CD4 response to HAART. It may present as focal disease away from the original site and reflects immune activation to dead or dying mycobacteria, or previously unrecognised tuberculosis; treatment with non-steroidal anti-inflammatory agents or corticosteroids is usually successful.
NURSING MANAGEMENT
The nursing management of patients infected with HIV is identical to those uninfected. However there are several other considerations that must be addressed which are not exceptional to HIV though arise more often in this setting.
Confidentiality
Unfortunately there remains a large stigma attached to the diagnosis of HIV and a patient’s wish to maintain confidentiality about the diagnosis to themselves and their family must be respected at all times. Where the clinical condition of the patient does not allow for informed consent to counsel for an HIV antibody test, the decision to perform this test should be made by the senior physician after careful assessment as to how the knowledge of the result will affect management. The patient’s relatives or partner should not be approached.
Medication adherence
Antiretroviral therapy is effective so long as the patient adheres to the medication. When admitted to hospital it is essential that a detailed list of the patient’s medication and dosages is obtained and subsequently administered at the correct time. Omission of dosages of antiretrovirals encourages both resistance in the virus and poor adherence by giving the patient the wrong message that it is safe to miss medication. Where feasible for adherent patients, self-medication should be encouraged.
Control of infection
Standard infection control procedures should be followed for all patients, however when carrying out a procedure on an infected patient such as nasopharyngeal aspiration, it is important to wear a mask and eye protection to protect from splashes. However if a needle stick injury or mucosal splash occurs, medical advice concerning post-exposure HIV prophylaxis should be sought immediately (and ideally should be commenced within two hours of exposure). Aseptic non-touch technique (ANTT) should be used in the management of all invasive lines.
Disclosure
Patients newly diagnosed with HIV will require a lot of emotional support. The diagnosis invariably comes as a shock and patients may find it difficult to disclose to family and friends, however it is important that with time they are encouraged to do so particularly when individuals may have been at risk of acquiring the infection (sexual partners, children of an HIV positive mother, previously shared needles or razors). If the hospital HIV services have not already been involved, an urgent referral should be made to allow post-test counselling and specialist HIV input to be given as well as access to other support services.
SUMMARY
Despite the advances in diagnosis, pharmacological therapy and neurosurgery, CNS infections are associated with high morbidity and mortality. Successful management requires early intervention with pharmacological therapy and vigilance for early signs of complications.
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