Meningitis is the inflammation of the pia and arachnoid membranes (leptomeninges) that surround the brain and spinal cord [14]. The classification of meningitis is based on its duration and recurrence and includes: acute (aseptic and septic) syndromes (<4 weeks duration), recurrent meningitis (multiple acute episodes of <4 weeks each), and chronic meningitis (>4 weeks duration).

Acute aseptic meningitis, which is defined by negative routine screening cultures and stains of cerebrospinal fluid (CSF), is the most common form of meningitis [15]. The clinical syndrome starts with high-grade fever and severe headache associated with nausea, vomiting, pharyngitis, diarrhea, neck stiffness, and photophobia. Seizures are not a common manifestation. Rapid and complete recovery is the usual course. Viral infections are commonly the cause of aseptic meningitis, and the most common are the enteroviruses (echovirus, coxsackie A and B, poliovirus, and the numbered enteroviruses) [15, 16]. Other causes of aseptic meningitis include: Human immunodeficiency virus (HIV), parasites, rickettsiae and mycoplasma, and autoimmune diseases such as Behçet’s disease, Kawasaki disease, and Vogt-Koyanagi-Harada disease [14]. Malignancies and drug reactions have also been implicated. In a population-based study, the 20-year risk for unprovoked seizures was 2.1% after aseptic meningitis, not higher than the general population risk for unprovoked seizures [17].

Acute septic meningitis is caused by a bacterial infection and inflammation of the meninges. It is a neurologic emergency with mortality rates as high as 15–33% even in hospitalized patients treated with antibiotics [18, 19]. The classic presentation of septic meningitis includes an acute onset over hours to days of a fever, headache, reduced alertness, and signs of meningeal irritation. The incidence of seizures in bacterial meningitis has been reported as 5–28% of cases, and often (76%) they occur within the first 24 h of presentation [20–23]. Seizures are an independent predictor of mortality (34% mortality in patients with seizures compared to 7% without seizures; odds ratio 17.6). Predictors of prognosis in bacterial meningitis include: age greater than 60 years, coma at onset or focal seizures within the first 24 h of admission (72% vs. 18% mortality among those with and without early onset seizures, respectively) [20]. In one retrospective study of 445 patients with acute bacterial meningitis, seizures had focal onset in 7%, generalized in 13%, and not characterized in 3% [20].

The effective evaluation and treatment of patients with bacterial meningitis involves early initiation of empiric antibiotics, collection of CSF to determine causative organism and antibiotic sensitivities, as well as adjunctive therapies (steroids) and additional evaluations (imaging, cEEG) in select patient populations. Delay in initiation of antibiotic therapy in patients who are septic has been shown to increase mortality by 7.6% for every hour of delay [24, 25]. Emergent treatment (<3 h from hospital admission) with empiric antibiotic therapy has been also been shown to reduce the risk of mortality at 3 months [19]. Although significant controversy exists as to the role of steroids, a recent Cochrane review supported the use of corticosteroids to reduce hearing loss and additional neurologic sequelae of bacterial meningitis [26]. The occurrence of seizures in patients with meningitis may indicate a cortically based complication (empyema, stroke, venous thrombosis), which merits neuroimaging studies (ideally a contrast enhanced CT scan or MRI). Cortical venous thrombosis usually presents with seizures and focal neurological signs albeit an uncommon event during bacterial meningitis (only 5.1% of autopsies of patients who died from meningitis had septic cortical vein thrombosis in a large series) [27]. Patients with persistent alteration in mental status or coma should undergo an EEG to rule out sub-clinical seizures. In one series continuous EEG (cEEG) was decisive or at least contributed to clinical decision-making in 12/13 patients with intracranial infection [28]. Since the widespread use of the vaccine for Haemophilus influenzae type B, Streptococcus pneumoniae has replaced it as the most common cause of acute community-acquired bacterial meningitis in industrialized countries. S. pneumoniae and Neisseria meningitides now account for the majority of cases of meningitis [25]. The rising incidence of beta-lactam-resistant pneumococci has to be considered when choosing a regimen for empiric antibiotic therapy [29]. Empiric antibiotic therapy for a suspected bacterial CNS infection should be given in consideration with the patient’s age, competence of the immune system, and associated morbidities. An immune competent adult (ages 2–50) should be started on a third generation cephalosporin (ceftriaxone – 4 g/d or cefotaxime – 8–12 g/d) in addition to vancomycin (30–60 mg/kg per day (8–12 h) to achieve serum trough concentrations of 15–20 μg/mL), and the addition of ampicillin (12 g/d) for patients over age 50 who are more susceptible to S. agalactiae and Listeria monocytogenes [30]. An immune compromised adult should be treated with ampicillin, vancomycin (2–3 g/d), and a fourth generation cephalosporin such as cefepime (6 g/day), which has more stability against B-lactamase producing organisms and pseudomonas. Neurosurgical patients, including those with CSF shunts, and head trauma patients require both gram positive and negative coverage with a recommended combination of vancomycin and ceftazidime (6 g/d), cefepime (6 g/day) or meropenem (6 g/day) [30].

Recurrent meningitis can be due to infectious and non-infectious causes. Viruses are the most likely infectious agents. Mollaret’s meningitis is a type of recurrent aseptic meningitis most frequently associated with herpes simplex type II virus. The clinical presentation may resemble aseptic meningitis, with headache (100%), photophobia (47%), self-reported fever (45%), meningismus (44%), and nausea and/or vomiting (29%) [31]. Seizures are part of the clinical presentation of Mollaret’s meningitis [32].

Chronic meningitis has a non-specific presentation, with variable fever, headache, neck rigidity, and signs of parenchymal involvement, such as altered mental status, seizures, or focal neurologic deficits [14]. Infectious causes include: cryptococcus, coccidiomycosis, blastomycosis, histoplasmosis, aspergillosis, mycobacterial, and neurosyphilis [33]. Non-infectious causes include neoplasms, neurosarcoidosis, and CNS vasculitis [14]. Seizure treatment in the context of acute or chronic meningitis is not different from the treatment offered for other causes. Details can be found in the chapter “Management of Critical Care Seizures” and “Management of status epilepticus.”

Encephalitis is an acute infection of brain parenchyma and should be suspected in patients who present with altered mental status and signs of cerebral dysfunction, and often accompanied by a fever. There are numerous viral causes of encephalitis of which the most common are: Herpes simplex virus (HSV) (the most common sporadic viral cause of encephalitis), varicella zoster virus (VZV), cytomegalovirus (CMV) , human herpesvirus 6, Epstein Barr virus (EBV), JC virus, enteroviruses, rabies as well as several arthropod-borne infections (Japanese encephalitis virus (the most common epidemic viral cause), West Nile virus, St. Louis encephalitis virus, La Crosse virus, Murray Valley encephalitis, Powassan virus, Tickborne encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, and deer tick virus [34]. Specific viruses can have characteristic presentations, such as shingles associated with VZV, and several of these infections only present in patients who are immunocompromised (CMV, JC virus) [34]. The majority of patients with encephalitis have abnormal EEG findings, of which the most frequent EEG characteristics are uni- or bilateral periodic discharges, focal or generalized slow waves, and electrical seizures [35]. A normal EEG in acute encephalitis had a strong predictive value for a low relative risk of death in one series. Additionally, those patients with infectious causes of encephalitis were more likely to have nonreactive EEGs than those with an inflammatory or autoimmune etiology [35].

Seizures, both focal and generalized are a common manifestation of the viral encephalitides. These can be grouped as acute symptomatic seizures (those that occur within 7 days of an infection) and as unprovoked seizures (those that occur after 7 days). The estimated rate of seizures within the acute period is from 2 to –67%, however, this likely underestimates the total number given limited availability of EEG, subtle symptomatic seizures, and a high incidence of nonconvulsive seizures in comatose patients [36, 37]. For patients who have had viral encephalitis, there is thought to be 16 times the likelihood of developing unprovoked seizures later in life, and for those that have had seizures during the acute phase, the risk is 22 times that of the general population [36]. In another population-based study, Annegers et al. found that the risk of developing unprovoked seizures within 20 years was 22% in patients with viral encephalitis and early seizures, 10% for those with viral encephalitis without early seizures, 13% in patients with bacterial meningitis and early seizures, and only 2.4% in patients with bacterial meningitis without early seizures [17]. Treatment of seizures with epilepsy surgery may be a better option in cases where there is a clearly localized focus. In a series of 38 patients who developed medically intractable partial seizures, Marks et al. found that 16 of them had a history of meningitis and 22 had encephalitis . Meningitis was pathologically associated with mesial temporal sclerosis and encephalitis with neocortical foci. However, in patients with encephalitis at less than 4 years of age, seizures were also associated with mesial temporal sclerosis [38].

Human Immunodeficiency Virus (HIV) , a lentivirus which attacks the immune system and can lead to acquired immunodeficiency syndrome (AIDS), is estimated to affect 1.2 million persons living in the USA as of 2011 [71]. HIV poses a risk to patients for developing seizures for multiple reasons, including opportunistic infections, direct neurotropic effects of HIV, and the drugs that are used to treat the infection. New-onset seizures are common in HIV patients, occurring in 3–17% of patients [72]. Although most seizures are usually seen in the advanced stages of the disease, they may also occur early or as the presenting symptom of HIV infection [73].

In the majority of patients, seizures are associated with an underlying intracranial mass lesion, infection, or metabolic disturbance. Intracranial mass lesions, including opportunistic infections, neoplasms, and cerebrovascular disease make up almost half of neurological disorders in AIDS patients. These are all commonly associated with seizures. In one series of patients with new-onset seizures, generalized seizures occurred in 94% of patients, partial in 26%, and status epilepticus in 14%. An associated space occupying lesion or CNS infection was found in the majority of cases of patients who seized. The most common causes include: cerebral toxoplasmosis, CNS lymphoma , progressive multifocal leukoencephalopathy, cryptococcal meningitis, and infarction [72, 74]. Toxoplasmosis, the most common cause of intracranial mass lesions in AIDS, presents with seizures as an early manifestation in 15%–40% [75]. The second most common intracranial mass lesion producing seizures in AIDS patients is CNS lymphoma. Progressive multifocal leukoencephalopathy (PML), although a white matter disease without significant mass effect, can produce seizures, either partial or generalized. The highest risk factor for PML lesions to cause seizures was juxtacortical location (RR of 3.5) [76]. Meningitis and encephalitis are a frequent cause of seizures in HIV-infected patients, with cryptococcal meningitis being the most frequent meningo-encephalitis producing seizures [77]. There are several other less common causes for seizures in HIV-infected patients, including subacute sclerosing panencephalitis, aseptic meningitis, neurosyphilis, herpes zoster leukoencephalitis, and cytomegalovirus encephalitis. Other focal CNS lesions include brain abscess (tuberculous, cryptococcal, nocardial), tuberculomas, syphilitic gummas, and cerebrovascular diseases. [73, 78]

The pathophysiology of generalized seizures and status epilepticus in HIV-infected patients may be explained by lowered threshold for cortical excitability and impaired inhibitory mechanisms for terminating seizures once started. Specifically, HIV- or immune-related toxins produced by interactions between macrophages, microglia, monocytes, and astrocytes may injure or kill neurons [78]. Neurotoxic substances, including eicosanoids, platelet-activating factor, quinolate, cysteine, cytokines, and free radicals, increase glutamate release, activate voltage-dependent calcium channels and NMDA receptor-operated channels, leading to calcium influx and neuronal death. Postmortem neuropathological examination of the brain in 17 patients with HIV and otherwise unspecified etiologies for the seizures showed microglial nodules or multinucleated cells or both in six patients, suggesting that the HIV infection was the likely cause of the seizures. [74]

The medications used to treat HIV are also felt to be responsible for many cases of new-onset seizures. In one series it was found that 18% of patients with no identifiable etiology were taking foscarnet, which was postulated to be epileptogenic [73]. Additionally, drug–drug interactions often complicate the treatment of seizures in patients taking anti-retrovirals. As a result of hepatic enzyme induction and drug–disease interactions there is often a reduced concentration of protease inhibitors, which can lead to diminished antiviral efficacy. The choice of anticonvulsant is ideally one which has no effect on viral replication, has limited protein binding, and does not have effects on the cytochrome P450 system [79]. These include gabapentin, topiramate, levetiracetam, lacosamide, pregabalin, or lamotrigine, all of which have limited interactions with other drugs or no effect on the P450 system. Most nucleoside reverse transcriptase inhibitors are renally metabolized through glucuronidation by enzyme systems different than the cytochrome P450, thus not affecting the hepatically metabolized anti-epileptic drugs. On the other hand, the non-nucleoside reverse transcriptase inhibitors (like nevirapine, delaviradine, and efivanenz) use the cytochrome P450 system and may lead either to induction (efivarenz) or inhibition (nevirapine and delaviradine), affecting the anti-epileptics that use these systems.

It is critical to remember that the HIV-protease inhibitors decrease the functioning of the hepatic CYP3A enzyme system. In one study, carbamazepine dosed at 200 mg/day for post-zoster neuralgia, reached anti-epileptic therapeutic levels in an HIV patient receiving triple anti-retroviral therapy (indinavir, zidovudine, and lamivudine). Additionally complicating this picture, indinavir plasma concentrations decreased significantly and HIV-RNA became detectable during the period of carbamazepine treatment [80]. Hypoalbuminemia, a common situation in the ICU and in HIV seropositive patients should also be considered. Highly protein bound anti-epileptic (phenytoin, valproic acid, carbamazepine, clonazepam, diazepam) may displace highly protein bound anti-retroviral drugs (delaviradine, efivanez, saquinavir, vitonavir, nelfinavir, lopinavir, and ampenavir) or vice versa, leading to toxic free concentrations of either drug [81]. The HIV-induced hypergammaglobulinemia may also predispose patients to hypersensitivity reactions from anti-epileptics, especially phenytoin. In vitro studies have indicated that there may be stimulation of HIV replication when using valproic acid. In a retrospective study of manic HIV(+) patients who were taking divalproex sodium and anti-retrovirals, however, the HIV-1 viral load did not increase [82, 83].

Seizures are generally a poor prognostic indicator in HIV-infected patients and will likely recur. It is therefore recommended that patients experiencing a first seizure without a reversible cause be treated. The reported incidence of convulsive status epilepticus is 8–18% and is often associated with poor prognosis [72, 74, 84]. In one study of 42 patients with HIV infection and status epilepticus, the median duration of status was 2.0 ± 10 h. Most patients (88%) responded to IV benzodiazepine or phenytoin treatment . Nevertheless, (29%) patients died and (36%) developed new neurologic deficits [75]. The most common EEG finding is non-specific diffuse slowing, while focal slowing and epileptiform activity was infrequent. EEG showed generalized and diffuse slowing only in nine patients, regional slowing in 14 patients and regional slowing and epileptiform discharges in one patient. Only 14 of the patients had normal EEG [74, 77].

A brain abscess is a purulent infection of brain parenchyma that often occurs in patients with predisposing factors such as an immunocompromised state, disruption of natural protective barriers, or a systemic source of infection. The incidence of brain abscesses is thought to be 0.3–1.3 per 100,000 people per year, but is considerably higher in patients with HIV/AIDS. In one systematic review of the literature, the most commonly isolated species were Streptococcus (34%) and Staphylococcus (18%), however, numerous other organisms have been isolated including: gram-negative enteric species, pseudomonas, actinomycetales, parasites, and fungi [85]. The route of transmission is usually contiguous spread from a local primary focus such as paranasal sinusitis, otitis media, mastoiditis, or penetrating head trauma. Ten percent of cases spread hematogenously, usually from a pulmonary source such as bronchiectasis or lung abscess, but also from heart valves (infective endocarditis) or conditions causing a right to left shunt such as cyanotic heart disease in children [86].

The most common clinical presentation is a headache; fever and alterations in consciousness are uncommon. Focal deficits can also occur based on the site of the abscess [86]. In a review of the literature, seizure was the initial presentation of patients with brain abscesses approximately 25% of the time [85]. In one series in which 70 patients were followed after cerebral abscess, approximately 70% of patients developed seizures [87]. In a group of 205 patients enrolled in a 22-year retrospective study, 48 patients had seizures, 27 of whom had early seizures (those during the time of the bacterial infection), and 21 had late seizures. For those patients who developed seizures, the mortality rate was 23% [88].

Treatment of brain abscess requires antibiotic therapy, surgical intervention, and some authors have suggested the use of prophylactic anticonvulsants given the frequency of seizures [89]. Empiric antibiotic coverage with a third generation cephalosporin, vancomycin, and metronidazole is often appropriate for patients following neurosurgical procedures. For patients who have undergone organ transplantation, the addition of trimethoprim–sulfamethoxazole or sulfadiazine covers nocardia species, and voriconazole would cover fungal species, especially aspergillus. In the initial treatment of HIV-infected patients , coverage for toxoplasmosis (pyrimethamine plus sulfadiazine) is recommended, but only for those with positive test results for antitoxoplasma IgG antibodies. Treatment for tuberculosis (isoniazid, rifampin, pyrazinamide, and ethambutol) should be considered in those from endemic areas and in those with HIV infections [86]. It is recommended that anticonvulsants be continued for a period of 2 years after surgery and normalization of the EEG [90].

Epidural abscesses and subdural empyemas are bacterial infections within the extra cerebral spaces. Epidural abscesses, typically present with headache, fever, and nausea. Neurological symptoms and complications are quite rare due to the protective effect of the tight adherence of dura to overlying skull. A subdural empyema, which is most commonly situated over the cerebral convexity, can cause altered level of consciousness, focal neurologic deficits, and seizures. The spread of infection through the subdural space can cause inflammation of the brain parenchyma and result in edema, elevated intracranial pressure, septic thrombophlebitis, venous infarction, or mass effect [91]. These extra-axial infections may result as a complication of trauma, neurosurgical procedures, meningitis, sinusitis, and other extracranial sources of infection. Subdural empyemas and epidural abscesses are commonly caused by staphylococcal species. Forty percent of cases can be polymicrobial. Streptococci, followed by staphylococcal organisms and anaerobes such as Propionebacterium and Peptostreptococcus are the most common causes [91].

Seizures are uncommon with epidural abscess and relatively common with subdural empyema. In a period of 14 years, 25 patients were retrospectively identified in a Taiwanese hospital (15 with subdural empyema and nine with epidural abscess). Seizures were found in 54% of patients; only in one patient with epidural abscess and in 12/15 (80%) patients with subdural empyema [92]. The same pattern of rarity of seizures with epidural abscess and relative frequency with subdural empyema is also encountered in children [93]. In a study reporting the incidence of early and late seizures after subdural empyema, early seizures occurred at a similar rate (62.5%) as that of late seizures (63%) in patients who survived. All patients received anticonvulsant prophylaxis, which was continued for 12–18 months. Early seizures were more common in cases with paranasal sinusitis, but did not correlate with occurrence of late epilepsy. Of those patients with follow-up, 29% who had early seizures had further attacks; of patients with no early seizures, 42% developed epilepsy during the follow-up period, most within the first 2 years. No factors predicting the occurrence of late seizures were identified [94].

Subdural empyema can be treated with intravenous antibiotic therapy, with a third-generation cephalosporin and metronidazole, followed by early surgical evacuation [95]. A prophylactic anticonvulsant is recommended. Craniotomy is generally preferred to multiple burr holes [94]. Antibiotics should be given intravenously for at least 2 weeks followed by oral therapy for up to a total of 6 weeks [95].

Ventriculitis is a pyogenic infection of the ventricular cavity. The ventricles may act as a reservoir for persistent inflammation, which may block the CSF outflow tracts and act as a brain abscess. The most common infecting organisms are Staphylococcal species. Thirty percent of all meningitis cases may be associated with ventriculitis while over 90% of neonatal meningitis is complicated by ventriculitis. Therefore, it should be considered in patients with meningitis who do not quickly respond to antibiotics. Ventriculitis is frequently (5%) associated with CSF shunts, intracranial devices, intrathecal chemotherapy, and rupture of a periventricular abscess [91, 96, 97].