Stroke, including hemorrhagic
Low antiepileptic drug levels
Alcohol withdrawal
Drug withdrawal (benzodiazepine, barbiturate)
Anoxic brain injury
Metabolic disturbances
Infection (bacterial meningitis, herpes encephalitis, brain abscess)
Traumatic brain injury
Brain neoplasm
Remote brain injury
Febrile seizures (in children)
In a substantial minority of frustrating cases, however, clinicians are unable to firmly ascertain the etiology of SE on the basis of the information obtained from the medical history and the initial work-up. In this scenario, which often involves a previously healthy young adult or child, a long list of diagnostic tests is typically ordered that will sometimes lead to the correct diagnosis [5].
Finding the cause of SE serves at least two major purposes: therapeutic and prognostic. The management of SE is unusual among neurologic disorders, as the initial treatment almost always focuses on the symptomatic control of seizures prior to determination and treatment of the underlying cause [6]. Prompt cessation of both generalized convulsive SE (GCSE) and nonconvulsive SE (NCSE) is associated with better outcome [7, 8]. Once seizures are terminated, however, and perhaps even more importantly if they persist despite intensive anti-seizure treatment, the treatment of the underlying etiology needs to be undertaken. Diagnostic and therapeutic delay contributes to poor outcome in a variety of conditions that can cause SE, such as viral or autoimmune encephalitides [9, 10]. Further, seizure control might only be achieved provided the underlying cause is treated. An increasing number of studies have shown that etiology is one of the strongest independent determinants of outcome after SE [11–13]. It is indisputable that SE due to an easily reversible systemic etiology (acute poisoning or withdrawal) is less likely to be associated with long-term disability or epilepsy than SE caused by an acute neurologic catastrophe. In some situations, SE might be the harbinger of a chronic neurologic disease, with long-term therapeutic and prognostic implications. New-onset status epilepticus might for instance represent the initial manifestation of a mitochondrial disorder [14]. Even if no specific cure is available, affected patients and families can be provided with early counseling and support once the diagnosis is made.
Virtually any neurologic disorder affecting the cerebral cortex can potentially result in seizures and SE. Indeed, more than 180 uncommon causes of SE have been reported [15]. They can be conveniently divided into four categories:
Inflammatory and autoimmune encephalitis
Uncommon infectious encephalitis
Genetic and congenital disorders
Toxin, drug, and intervention-related disorders
It is impossible to review every single cause of SE. Instead, we will focus on the clinical entities that can lead to SE as their initial or early manifestation and will pose a diagnostic challenge to the clinician. We will only briefly mention those that are likely to be known already at the time SE occurs, but some syndromes associated with a peculiar type of SE will be discussed.
Finally, it is important to recognize that in a few cases of de novo refractory SE, often preceded by a mild febrile illness, no clear etiology will be identified despite an extensive work-up. These cases have been described under several acronyms, including NORSE (new-onset refractory status epilepticus) in adults [16] and FIRES (febrile illness-related epilepsy syndrome) in children [17]. These entities and their possible etiology will be discussed. We will close the chapter by providing a practical approach to those difficult cases.
Inflammatory and Autoimmune Encephalitis
This category comprises a wide spectrum of disorders (Table 8.2), some of which have only recently emerged as causes of SE. In most recent series of encephalitis, autoimmune and inflammatory cases represented 8–22% of all causes [18–20]. Inflammatory causes represent only 2.5% of SE [21] but this proportion might be higher in patients with refractory SE [5, 22].
Table 8.2
Inflammatory causes of status epilepticus
Paraneoplastic encephalitis | Anti-Hu |
Anti-Ma2/Ta | |
Anti-Ri | |
Anti-CV2/CRMP-5 | |
Anti-amphyphysin | |
Seronegative | |
Autoimmune encephalitis | Anti-NMDA receptor |
Anti-VGKC complex (especially anti-LGI1) | |
Anti-GABA(A) receptor | |
Anti-GABA(B) receptor | |
Anti-AMPA receptor | |
Anti-glycine receptor | |
Anti-GAD | |
Rasmussen encephalitis | |
Multiple sclerosis, ADEM | |
Steroid-responsive encephalopathy with autoimmune thyroiditis (SREAT) | |
Primary angiitis of the CNS | |
Systemic autoimmune disorder | Macrophage activation syndrome/hemophagocytic lymphohistiocytosis |
Systemic lupus erythematosus | |
Sjögren (and anti-Ro/SSA) | |
Thrombotic thrombocytopenic purpura | |
Behçet syndrome | |
Celiac disease |
Paraneoplastic Limbic Encephalitis
Paraneoplastic limbic encephalitis is characterized by cognitive impairment, especially in memory; behavioral changes; seizures; and sleep disturbance [23]. Pathologic examination and brain magnetic resonance imaging (MRI) show evidence of inflammation in the limbic structures, particularly the mesial temporal lobes. In line with this preferential involvement, seizures are most often of the complex partial type, but they can generalize. Signs of wider involvement of the central and peripheral nervous systems, such as widespread encephalomyelitis, cerebellar degeneration, and sensory neuronopathy, are frequent, especially in the syndrome of diffuse encephalomyelitis associated with the anti-Hu antibody [24]. Hypothalamic dysfunction is a common feature of the encephalitis associated with Ma2/Ta antibodies and testicular cancer [25]. Status epilepticus as the initial or prominent manifestation of paraneoplastic encephalitis is uncommon but has been reported, mostly with the anti-Hu antibodies [5, 26–30].
CSF analysis is almost invariably abnormal, showing elevated protein levels and pleocytosis. The diagnosis is made by identification in the serum of one of the many known antibodies (see Table 8.2). The antibodies recognize intracellular antigens shared by the tumor and the neurons. They are not believed to play a direct pathogenic role and are mostly biomarkers. Neurologic involvement is attributed to a cell-mediated immune reaction. Paraneoplastic limbic encephalitis precedes the diagnosis of cancer in up to half of the cases. Its occurrence should prompt thorough and repeated investigations for an occult neoplasm, most frequently small cell lung carcinoma (see Table 8.2). Guidelines for the screening for occult malignancy have been published. Whole-body fluorodeoxyglucose positron emission tomography (FDG-PET) is superior to CT in demonstrating occult neoplasms [31]. A negative PET/CT scan does not rule out underlying cancer, and repeating a PET/CT scan after a 6-month interval is recommended, followed by screening every 6 months up until 4 years if testing remains unrevealing. Cases of seronegative paraneoplastic limbic encephalitis still occur and may cause SE. Whether or not this should justify a thorough investigation for an occult neoplasm in all patients with cryptogenic SE is unclear.
Response to immune therapies is often disappointing. Successful treatment of the underlying neoplasm is sometimes associated with partial neurologic improvement.
Encephalitis Associated with NMDA Receptor Antibodies
Although the clinical entity was described only 10 years ago [32] and the antibody discovered a few years later, the encephalitis associated with N-methyl-D-aspartate (NMDA) receptor antibodies has quickly emerged as the most common encephalitis associated with antibodies against a neuronal surface antigen [18–20]. In a recent publication from the California Encephalitis Project, it was four to five times more frequent than Herpes Simplex, Varicella Zoster and West Nile virus encephalitides, and as frequent as enterovirus encephalitis [33]. Most patients are young women but the syndrome can occur at any age [34]. A prodromal nonspecific febrile illness is common. It is followed a couple of weeks later by behavioral changes, short-term memory loss, delusions, and hallucinations. Seizures and SE mostly occur at this stage. They are most commonly of the generalized tonic-clonic type, but partial complex seizures have been reported. For an unknown reason, male patients tend to present more frequently with seizures at onset than female patients [35]. Status epilepticus can be refractory [5]. Patients then progress to a severe catatonic stage, during which they alternate between periods of akinesia and periods of violent agitation. At this stage, most patients develop typical orofacial dyskinesia, autonomic instability, and hypoventilation, often requiring prolonged ventilator support.
Electroencephalography (EEG) occupies a central place in the diagnosis of the syndrome. In most cases, it shows continuous generalized delta activity, which is often rhythmic and fluctuates in frequency. In as many as 50% of cases, the EEG shows a peculiar and disease-specific pattern of generalized rhythmic delta activity with superimposed beta or even gamma activity, termed ‘extreme delta brushes’ because of their resemblance to the delta brushes of neonates [36]. Some have argued that this pattern represents SE, but this author finds it doubtful as there are no consistent clinical manifestations and response to aggressive anti-seizure treatment is often disappointing.
A few patients may also exhibit nonconvulsive status epilepticus (NCSE), with abnormal generalized paroxysmal fast activity or tonic SE during the catatonic stage (Fig. 8.1). CSF analysis is abnormal in more than 90% of cases, most commonly showing a mild lymphocytosis [34]. The antibody is not always found in the serum and should be looked for in the CSF. Brain MRI sometimes shows T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities in neocortical areas or, less commonly, in the mesial temporal lobes, basal ganglia, or brainstem. Approximately half of the female patients have an ovarian teratoma. Pelvic MRI is more sensitive than CT scan and ultrasound, but the tumor can be microscopic and escape imaging techniques. Treatment includes tumor resection and immune therapy (see Chap. 17).
Fig. 8.1
Ten-second electroenchepalography (EEG) excerpts from continuous recording in a 19-year-old woman with anti-NMDA receptor encephalitis. During most of the recording, the EEG showed a typical pattern of extreme delta brushes, characterized by continuous rhythmic delta activity with superimposed low voltage beta activity (a). Occasionally, brief bursts of generalized paroxysmal fast activity occurred with little accompanying delta activity (b). The patient also exhibited frequent brief generalized tonic seizures. The EEG correlate was often difficult to distinguish from muscle artifact, and the patient was transiently paralyzed to better observe ictal discharges (c). EEG settings: low-frequency filter: 1 Hz; high-frequency filter: 70 Hz; notch filter: off
Encephalitis with Voltage-Gated Potassium Channel Complex Antibodies
Once thought to target the potassium channels, antibodies directed toward the voltage-gated potassium channel (VGKC) complex are now known to most frequently bind other components of a multiprotein complex that anchors the channels in the neuronal membrane, mainly the leucine-rich, glioma-inactivated 1 (LGI1), and contactin-associated protein-like 2 (Caspr2), and only rarely the channels themselves [37]. LGI1 antibodies are associated with a typical course of limbic encephalitis, while Caspr2 antibodies are more commonly associated with neuromyotonia and Morvan syndrome [37]. Low titers of antibodies can be seen in individuals with various unrelated non-autoimmune disorders and in some patients with peripheral nerve hyperexcitability, while high titers are the rule in patients with clear limbic encephalitis. This type of encephalitis is more common in men and occurs mostly after the age of 40 years. Seizures occur in 80% of cases and can be partial complex or secondary generalized seizures. Ictal autonomic manifestations, such as piloerection, have been reported. Hyponatremia (<130 mEq/l) occurs in 30–60% of cases due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and should raise suspicion of the diagnosis.
A peculiar type of seizure, termed faciobrachial dystonic (tonic) seizure, has been described recently in a subset of patients with anti-LGI1 encephalitis [38]. These seizures occur frequently, up to hundreds of times per day, and are characterized by brief tonic contraction of the arm and face, either on one side or, more commonly, alternating between both sides. EEG changes during faciobrachial dystonic seizures vary but most often consist of diffuse attenuation or bursts of slow waves. Faciobrachial dystonic seizures precede the manifestations of limbic encephalitis and do not respond to anti-seizure medications. In contrast, immune treatment is efficacious and might prevent the development of cognitive impairment [39]. Complex partial SE may also occur rarely [5].
CSF analysis is most often normal. Brain MRI is abnormal in 50% of cases, and commonly shows hyperintensities in the mesial temporal lobes and sometimes, basal ganglia. Most patients with anti-VGKC complex antibodies do not have an associated neoplasm, but rare paraneoplastic cases exist, mostly related to small cell lung carcinoma and thymoma. Treatment with steroids, IV immunoglobulin (IVIG), or plasma exchange is efficacious, and most patients make a full recovery. Clinical improvement usually mirrors the decrease in antibody titer in the serum.
Encephalitis with Other Antibodies Against Neuronal Surface Antigens
Several syndromes of autoimmune encephalitis with antibodies against neuronal surface antigens have been described recently. They are even rarer than the encephalitis associated with NMDA receptor and VGKC complex antibodies, but some can cause SE.
Limbic encephalitis with GABA-B Receptor, AMPA Receptor and Glycine Receptor Antibodies. Patients with antibodies against the R1 subunit of the γ-aminobutyric acid B (GABA-B) receptor present with a typical form of limbic encephalitis, with prominent seizures and complex partial SE [43–46]. The antibodies may be absent from patients’ serum and detected only in the CSF. Half the cases are associated with a neoplasm, most commonly small cell lung carcinoma. Onconeural antibodies are identified in between one-third and one-half of these paraneoplastic cases, whereas non-paraneoplastic cases often present with other autoimmune diseases (including type 1 diabetes mellitus, idiopathic thrombocytopenia, and thyroiditis) or auto-antibodies (e.g., glutamic acid decarboxylase 65 [GAD65], thyroperoxidase [TPO], thyroglobulin [TG]). Most patients respond at least partially to immune treatment and tumor removal, and some make a full recovery.
Antibodies directed against the GluR 1 or GluR2 subunits of the AMPA receptor have been identified in the serum or CSF of patients with a typical course of limbic encephalitis with prominent psychiatric symptoms [46–48]. Most were middle-aged women. Similar to other antibodies against neuronal surface antigens, AMPA receptor antibodies may be absent from the patient’s serum and only detectable in the CSF. Patients may have an associated neoplasm, most commonly small cell lung carcinoma. Patients responded well to treatment (immune therapy with or without tumor removal) but most had recurrent relapses, even after tumor removal.
Glycine receptor (GlyR) antibodies have been reported mainly in association with “stiff person syndrome” and progressive encephalomyelitis with rigidity and myoclonus, but a few cases of limbic encephalitis with seizures and SE have been described [49]. An association with cancer is rare.
Encephalitis and Refractory Status Epilepticus with GABA-A Receptor Antibodies. High titers of antibodies against the α1, β3, or γ2 subunits of the GABA-A receptor were identified in the serum or CSF of patients with either a typical form of limbic encephalitis or de novo refractory SE and multifocal cortical MRI abnormalities [50, 51]. Similar to patients with GABA-B receptor antibodies, many patients had other autoimmune diseases (e.g., type 1 diabetes mellitus, idiopathic thrombocytopenia, thyroiditis, celiac disease), auto-antibodies (e.g., GAD65, TPO, TG, endomysium, VGKC complex, NMDA receptor) or both. Half of the patients who received immune therapies responded at least partially.
Encephalitis with Glutamic Acid Decarboxylase 65 Antibodies
Elevated titers of antibodies against GAD65 are found in patients with stiff person syndrome or with a specific form of cerebellar ataxia associated with type 1 diabetes mellitus. They are also present, at lower titers, in most patients with type 1 diabetes mellitus and no neurologic syndrome. GAD65 is an intracellular protein, and the pathogenic role of the auto-antibodies is debated, especially since the neurologic manifestations are so variable. Nonetheless, well-described cases of encephalitis or epilepsy associated with GAD65 antibodies have been reported [52–54]. Patients are mostly young women and exhibit a chronic course of limbic encephalitis. Both complex partial SE of temporal origin and opercular SE have been reported. Severe cases of generalized convulsive SE with autonomic instability have been described in a small group of children. These cases overlap with the syndrome associated with anti-GABA-A receptor antibodies. High serum titers of the antibody are typically found and, when tested, intrathecal synthesis is detected. Most cases are unrelated to cancer, but a few patients may have small cell lung carcinoma.
Status Epilepticus Due to Acute Disseminated Encephalomyelitis and Multiple Sclerosis
Patients with multiple sclerosis are at higher risk of seizures compared to the general age-matched population, possibly because of cortical demyelination and inflammation [55, 56]. Focal SE is possible but rare [57–59].
Steroid-Responsive Encephalopathy with Autoimmune Thyroiditis
Steroid-responsive encephalopathy with autoimmune thyroiditis (SREAT), previously called Hashimoto encephalopathy, manifests by various combinations of subacute encephalopathy (e.g., rapid-onset dementia, delirium, alteration of consciousness), movement disorders (e.g., myoclonus, ataxia, tremor), and stroke-like episodes [63]. Seizures occur in up to two-thirds of cases. Some patients have hypothyroidism or hyperthyroidism, and all show high serum titers of antibodies directed against thyroperoxydase (TPO) or thyroglobulin (TG). The patient’s response to steroids is usually striking. A few cases of isolated generalized convulsive SE or NCSE in association with high titers of thyroid antibodies have been reported [5, 64, 65]. Whether they represent a subtype of SREAT or a separate entity is unclear, especially since antibodies against neuronal surface antigens can be found in some patients with thyroid antibodies [50].
Status Epilepticus Due Secondary to a Systemic Inflammatory Disorder
The mechanisms by which systemic inflammation can lead to seizures and SE are multiple and overall poorly understood.
Seizures happen in approximately 15% of cases of SLE and are part of the primary diagnostic criteria [66]. Seizures often occur at SLE onset and tend to accompany disease flares. Generalized convulsive SE, NCSE, and complex partial SE have all been reported [67, 68]. Patients with anti-phospholipid antibodies and strokes are at higher risk, but cerebral ischemia is not the only cause of seizures [69]. Some patients with antinuclear antibodies also exhibit antibodies against neuronal surface antigens. The posterior reversible encephalopathy syndrome (PRES; see below), which frequently causes seizures and SE, is increasingly recognized as a complication of SLE and other systemic autoimmune diseases [70]. Other systemic inflammatory disorders that have been associated with SE are listed in Table 8.2.
Uncommon Infections
Seizures frequently complicate infections of the central nervous system [71], and SE is independently associated with worse outcome in this setting [19]. While encephalitis is often listed as a cause of SE, an infectious agent is identified in only a quarter to a third of cases [18–20, 72]. Type 1 Herpes Simplex, Varicella Zoster, and Enteroviruses are the most frequently identified pathogens. Aside from them, there is a dauntingly long list of uncommon viruses, bacteria, parasites, and fungi that can cause encephalitis and SE (Table 8.3). Not all pathogens that cause encephalitis have been linked to SE, but this is likely due in part to the limited description of seizures in most case series and the uneven use of continuous of EEG monitoring. The list of infections presented here should not be considered exhaustive, and a complete work-up is advised when an encephalitis is suspected. An approach consisting of the blind ordering of random tests should be discouraged. Rather, a diagnostic algorithm tailored to each patient and based on host and environmental factors, clinical presentation, and results from initial blood and CSF analysis and brain MRI, is recommended [73, 74] (Table 8.4).
Table 8.3
Uncommon infectious causes of status epilepticus
Categories | Pathogens |
|---|---|
Atypical bacteria | Bartonella hanselae |
Treponema pallidum | |
Coxiella burnetii | |
Mycoplasma pneumoniae | |
Orientia tsutsugamushi (Scrub typhus) | |
Shigella sp. | |
Chlamydia psittaci | |
Ehrlichia chaffeensis/Anaplasma phagocytophilum | |
Rickettsia spp. | |
Leptospira spp. | |
Viruses | Herpes viruses Cytomegalovirus Epstein–Barr virus Human Herpes Virus–6 |
Arboviruses Flaviviruses (Tick–borne complex/Japanese, West Nile, Saint–Louis, Murray Valley) Bunyaviruses (California, La Crosse, Toscana, Jamestown Canyon, Rift Valley Fever) Togaviruses (Eastern Equine, Western Equine) Reoviruses (Colorado Tick Fever) | |
Influenza A Influenza B Parvovirus B19 HIV Measles Rubella Mumps (parotitis) Hendra virus Polyoma viruses | |
Parasites | Paragonimiasis |
Cysticercosis | |
Plasmodium falciparum | |
Toxoplasma gondii | |
Acanthamoeba spp. | |
Balamuthia mandrillaris | |
Baylisascaris procyonis | |
Fungi | Paracoccidioidomycosis |
Mucormycosis | |
Absidiomycosis | |
Cryptococcus sp. | |
Histoplasma sp. |
Table 8.4
Clues to the etiology of status epilepticus
Clues | Etiology |
|---|---|
Immune treatment and status | |
Immunocompromised (AIDS, immunosuppressive drugs) | Cytomegalovirus, Human Herpes Virus-6, Varicella Zoster Virus, Human Immunodeficiency Virus, West Nile Virus, Mycoplasma tuberculosis, Cryptococcus neoformans, Histoplasma capsulatum, Toxoplasma gondii |
Immunosuppressive and chemotherapeutic agents | PRES and direct drug toxicity |
Substance abuse | |
Alcohol | Withdrawal, Subacute encephalopathy with seizures in alcoholism |
Injected drugs | Direct toxicity; also AIDS and related infections |
Ingestion | |
Unpasteurized milk | Tick-borne virus, Coxiella burnetii |
Star fruit | Caramboxin, oxalic acid |
Occupational exposure to toxic substances | Toxin-related |
Geographical factors (residence, recent travel) | |
Africa | West Nile virus |
Australia | Murray Valley encephalitis virus, Japanese encephalitis virus, Hendra virus |
Central and South America | Eastern Equine Virus, Western Equine Virus, Venezuelan Equine Virus, Saint-Louis Virus, Rickettsia spp. |
Europe | West Nile Virus, Tick-borne Virus, Ehrlichia chaffeensis/Anaplasma phagocytophilum |
India, Nepal | Japanese Virus |
Middle East | West Nile Virus |
Russia | Tick-borne Virus |
Southeast Asia, China, Pacific Rim | Japanese Virus, Tick-borne Virus, Nipah Virus |
Seasonal factors | |
Late summer/early fall | Arboviruses, Enteroviruses |
Winter | Influenza Virus |
Animal exposure | |
Cats | Bartonella henselae, Toxoplasma gondii |
Horses | Eastern Equine Virus, Western Equine Virus, Venezuelan Equine Virus, Hendra Virus |
Raccoons | Baylisascaris procyonis |
Rodents | Bartonella quintana, Eastern Equine Virus, Western Equine Virus, Tick-borne Virus, Powassan Virus, La Crosse Virus |
Sheeps and goats | Coxiella burnetii |
Swine | Japanese Virus, Nipah Virus |
Insect exposure, including travel to infested area | |
Mosquitoes | Eastern Equine Virus, Western Equine Virus, Venezuelan Equine Virus, Saint-Louis Virus, Murray Valley Virus, Japanese Virus, West Nile Virus, La Crosse Virus |
Ticks | Tick-borne Virus, Powassan Virus, Rickettsia spp., Ehrlichia chaffeensis/Anaplasma phagocytophilum |
Prodromal symptoms | |
Prominent behavioral and psychiatric features | Anti-NMDA receptor encephalitis |
Prominent memory issues | Limbic encephalitis, anti-VGKC complex encephalitis |
Respiratory symptoms | NORSE/FIRES, ADEM, Mycoplasma pneumoniae |
Gastrointestinal symptoms | NORSE/FIRES, ADEM |
General examination | |
Fever | Infectious or inflammatory encephalitis |
Rash | Cytomegalovirus, Varicella Zoster Virus, Human Herpes Virus-6, West Nile Virus, Enterovirus, Rickettsia rickettsii, Mycoplasma pneumoniae, Ehrlichia chaffeensis/Anaplasma phagocytophilum |
Excoriating skin lesion | Bartonella spp. |
Regional adenopathy | Bartonella spp., Mycoplasma tuberculosis |
Generalized adenopathy | Human Immunodeficiency Virus, Epstein–Barr Virus, Cytomegalovirus, West Nile Virus, Treponema pallidum, Toxoplasma gondii |
Retinitis | Cytomegalovirus, West Nile Virus, Bartonella henselae |
Parotitis | Mumps |
Hepatitis | Coxiella burnetii |
Respiratory tract findings | Cytomegalovirus, Venezuelan Equine Virus, Nipah Virus, Hendra Virus, Influenza, Adenovirus, Mycoplasma pneumoniae, Coxiella burnetii, Mycoplasma tuberculosis, Histoplasma capsulatum |
Neurologic examination | |
Acute lower motor neuron syndrome | Japanese Virus, West Nile Virus, Tick-borne Virus, Enterovirus (serotype 71, Coxsackie) |
Acute parkinsonism | Japanese Virus, Saint-Louis Virus, West Nile Virus, Nipah Virus, Toxoplasma gondii |
Prominent oro-lingual dyskinesias | Anti-NMDA receptor encephalitis |
Faciobrachial dystonic seizures | Anti-VGKC complex (LGI1) encephalitis |
Ataxia | Epstein–Barr Virus, mitochondrial disorder |
EEG | |
Extreme delta brushes | Anti-NMDA receptor encephalitis |
Extreme spindles | Mycoplasma pneumoniae |
Parieto-occipital epileptiform discharges and seizures | Mitochondrial disorder, PRES |
MRI | |
Prominent mesial temporal lobe involvement | Paraneoplastic and autoimmune limbic encephalitis, anti-VGKC complex encephalitis |
Basal ganglia | Saint-Louis Encephalitis Virus, La Crosse Virus, and Murray Valley Virus |
PRES images | PRES |
Stroke-like images | POLG1, MELAS |
CSF | |
Normal protein levels and cell count | Genetic disorder |
Elevated lactate | Mitochondrial disorder |
Eosinophils | Parasitic encephalitis |
Blood and serum | |
Elevated liver tests | Mitochondrial disorder (esp. POLG1), Rickettsia spp., Cytomegalovirus |
Atypical Bacteria
Cat-Scratch Disease. Bartonella henselae (or rarely, Bartonella quintana) causes cat-scratch disease, also known as regional lymphadenitis. It occurs mostly in children and presents as regional lymphadenopathy near the site of the inoculating bite or scratch from a cat. An excoriated macular or papular skin lesion can often be seen at the site of inoculation. Most patients also present with systemic symptoms, such as fever, fatigue, and myalgia. In 1–2% cases, a severe meningoencephalitis ensues and is often complicated by generalized convulsive SE [75–78]. Treatment includes anti-seizure medications and antibiotics (azithromycin and rifampin in children, or doxycycline and rifampin in adults).
Mycoplasma Pneumonia. A severe form of encephalitis causing refractory SE has been reported in association with Mycoplasma pneumoniae [5, 79, 80]. Most cases occurred in children and young adults and were preceded by a febrile upper respiratory illness. The diagnosis relied mostly on serology, while direct identification of the pathogen in the CSF by culture or PCR was often not reported or negative, suggesting that a large number of cases might result from a postinfectious immune process. A peculiar EEG pattern of transient extreme spindles has been reported in a two children with M. pneumoniae encephalitis [81, 82].
Uncommon Viruses
Cytomegalovirus. Cytomegalovirus (CMV) encephalomyelitis preferentially occurs in immunocompromised patients, especially those with AIDS or receiving immunosuppressive drugs after transplant, and is often due to reactivation of latent virus in individuals with a low CD4 cell count (<50 cells/µl). Involvement of the nervous system by CMV in immunocompetent patients is rare but well documented and constitutes the second most frequent manifestations of infection after gastrointestinal illness [83, 84]. Patients present with a combination of symptoms and signs of myelitis, encephalitis, meningitis, or radiculopathy. Extra-CNS involvement is frequent and includes hepatitis, colitis, pneumonitis and retinitis. CSF abnormalities are nonspecific and variable. Pleocytosis is usually absent or mild and consists predominantly of lymphocytes and monocytes. Elevated protein levels are also rare. Brain MRI may be normal but sometimes shows diffuse or patchy T2/FLAIR hyperintensities in the white matter; images of ventriculitis can also be seen and should suggest the diagnosis [85].
Epstein–Barr Virus. Neurologic complications of EBV infection are uncommon. In immunocompromised patients, it is typically associated with primary lymphoma of the CNS, while in immunocompetent patients it has been associated with a variety of neurologic manifestations, including cerebellitis, ADEM, encephalomyeloradiculitis, Guillain–Barré syndrome, and Bell’s palsy. Contrary to the case in HSV1 and CMV infections, the likely mechanism of EBV-associated neurologic complications is a postinfectious immune process. Encephalitis with seizures can occur with an initial EBV infection in children and young adults, usually in the absence of symptoms of infectious mononucleosis [86]. Isolated refractory SE has also been reported.
Human Herpes Virus-6. Acute Human Herpes Virus-6 (HHV-6) infection causes roseola in children and is associated with febrile seizures [87]. The virus is known to integrate in human DNA and can be detected in body tissues and fluids throughout the lifetime, including in asymptomatic individuals. It has been detected in a high proportion of surgical specimen of mesial temporal sclerosis [88].
HHV-6 reactivation after allogeneic hematopoietic stem cell transplantation is associated with a distinct syndrome of fever, rash and acute limbic encephalitis (referred to as post-transplant acute limbic encephalitis, or PALE) [89]. The incidence is higher after umbilical cord blood transplantation. As with noninfectious limbic encephalitis, temporal lobe seizures are frequent and can evolve to SE.
Arboviruses. Arboviral infections are an increasingly important cause of encephalitis worldwide, due to both the emergence of new strains and the expansion of known pathogens [90]. Fever, headache, malaise, myalgia, vomiting, and nausea precede the neurologic manifestation and occur within days after inoculation. A variety of symptoms and signs of meningoencephalomyelitis can occur. Seizures, sometimes evolving to SE, are common to almost all arbovirus encephalitides. Parkinsonism is common in Dengue, Japanese Virus, West Nile Virus, Eastern Equine Virus, and Western Equine Virus encephalitides. An acute lower motor neuron syndrome is frequent with Dengue, Japanese Virus, West Nile Virus, and Tick-borne Virus infections. Laboratory and imaging findings can be nonspecific or normal, particularly in the early stages of disease. CSF findings include lymphocytic pleocytosis with mild protein elevation. CSF glucose is usually normal, but low glucose levels can be seen. Rapid serum or CSF antibody assays are available for most of the arboviruses. Brain MR imaging may be normal in early or mild cases. Certain viruses have a predilection for certain areas of the brain. Japanese Virus can affect basal ganglia, brainstem, or spinal cord. The basal ganglia may also be involved in Saint-Louis, La Crosse, and Murray Valley encephalitides. A variety of nonspecific EEG abnormalities can be seen. Triphasic waves have been reported in West Nile Virus encephalitis.
Other uncommon infectious causes of SE, including parasites and fungi, are summarized in Table 8.3.
Genetic and Congenital Causes of Status Epilepticus
Epilepsy is a common trait of numerous genetic and congenital neurologic disorders (Table 8.5). A recent systematic review identified more than 120 genes whose mutations were associated with status epilepticus [91]. The vast majority of these mutations cause rare syndromes that are encountered primarily in neonates, infants, and children. Seizures and SE are only a part of a syndrome that also comprises other signs, such as dysmorphic features, cutaneous abnormalities, failure to thrive, organ failure, cerebral malformations, etc. Most of these disorders can be subdivided into those associated with inborn errors of metabolism, including mitochondrial disorders, malformations of cortical development, neurocutaneous syndromes, and epileptic encephalopathies. Seizures are often a nonspecific manifestation, and the diagnosis will often be known or suspected by the time SE occurs. Discussed below are the main examples in which SE might be the initial or only manifestation of a genetic disorder or in which its characteristics are so specific that they lead to the diagnosis.
Table 8.5
Genetic and congenital disorders causing status epilepticus
Chromosomal abnormalities | Angelman syndrome |
Wolf–Hirschhorn syndrome | |
Ring chromosome 20, 17, 14 | |
Fragile X syndrome | |
X-linked mental retardation syndromes | |
Inborn errors of metabolism | Disorders of amino acid metabolism D–and L–2–hydroxyglutaric aciduria D–glyceric academia Lysinuric protein intolerance Maple syrup urine disease Phosphoserine aminotransferase deficiency 3–phosphoglycerate dehydrogenase deficiency 3 – Methylcrotonyl-CoA carboxylase deficiency Hyperprolinemia |
Disorder of citric acid metabolism (Krebs cycle) Fumaric aciduria | |
Disorder of copper metabolism Wilson disease Menkes disease | |
Disorder of creatine metabolism Guanidinoacetate methyltransferase deficiency | |
Disorder of cytosolic protein synthesis Cytosolic glutaminyl–tRNA synthetase | |
Disorder of fatty acid metabolism Combined oxidative phosphorylation deficiency Carnitine palmitoyl–transferase II deficiency 3–hydroxyacyl–CoA dehydrogenase deficiency | |
Disorder of cerebral folate transport Folate transporter deficiency | |
Disorder of GABA metabolism GABA transaminase deficiency Succinic semialdehyde dehydrogenase deficiency | |
Disorders of glycine metabolism Glycine encephalopathy/nonketotic hyperglycinemia | |
Disorder of glucose transport Glucose transporter 1 deficiency | |
Disorder of glycosylation Asparagine–linked glycosylation defect | |
Disorders of lipid storage Gaucher disease type 3 GM2 gangliosidosis (Tay–Sachs) GM2 gangliosidosis (Sandhoff) Metachromatic leukodystrophy Adrenoleukodystrophy Peroxisomal biogenesis disorders Zellweger syndrome Refsum syndrome | |
Disorders of purine and pyrimidine metabolism Adenylosuccinase deficiency Beta–ureidopropionase deficiency Vitamin-responsive disorders Pyridoxine – dependent epilepsy Pyridoxal – 5′ – phosphate-dependent epilepsy Folinic acid-dependent epilepsy Cobalamin C/D deficiency Biotinidase deficiency/Multiple carboxylase deficiency Urea cycle defects Ornithine transcarbamylase deficiency Citrullinemia type 11 | |
Disorders of heme metabolism Acute porphyrias | |
Others Aicardi–Goutières syndrome 6 Alexander disease GM3 synthase deficiency Molybdenum cofactor deficiency Mucopolysaccharidosis type II (Hunter syndrome) 1–Phosphatidylinositol–4,5–bisphosphate phosphodiesterase beta–1 defects Nonketotic hyperglycinemia Pyruvate carboxylase deficiency | |
Progressive myoclonic epilepsies | Unverricht–Lundborg disease |
Lafora disease | |
Progressive myoclonic epilepsy type 3–7 | |
Myoclonus epilepsy and ragged-red fibers (MERRF) | |
Sialidosis—type 1 | |
Sialidosis—type 2 | |
Neuronal ceroid lipofuscinoses 2 (Jansky–Bielschowsky disease) | |
Neuronal ceroid lipofuscinoses 3 | |
Neuronal ceroid lipofuscinoses 6 (Kufs’ disease) | |
Early childhood epileptic encephalopathies and severe epilepsy syndromes of infancy and childhood | Dravet syndrome (severe myoclonic epilepsy in infancy)
Related posts: Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
Get Clinical Tree app for offline access
|
