Fig. 7.1
Herpes simplex encephalitis, subacute stage. Coronal FLAIR images (a, b) show dishomogeneous hyperintensity in the left temporal medial region and in the left insula. Note the mild enlargement of the temporal horn. In (c, d), T1-weighted images without (c) and with contrast medium (d) show cortical hyperintensity due to laminar necrosis, with hemorrhage in the left temporal lobe. No definite enhancement was present.
7.1.3 The Immune Status of the Host
The patient’s immune status is a fundamentally important aspect that must be taken into consideration from the very early stages of the disease, because it will help to indicate the set of aetiologies within which the patient’s condition can most likely be framed.Immunodeficiency occurs in four main clinical situations: HIV infection, cancer, bone marrow and organ transplants, and immunomodulatory therapies. Old age has to be considered a condition of immune depression, per se. In all the aforementioned conditions, the nervous system is particularly vulnerable both to opportunistic infections and to infections that commonly affect immunocompetent individuals.
The relations between immunodeficiency, underlying disease, and neurotropism of viruses are highly complex. Some opportunistic infections are known to occur only in a specific setting of immunosuppression, or in a specific phase of a given disease. Still, in only a few select cases has the experience of recent years been translated into accurate definitions of the risk factors, clinical and biological profiles, survival rates, and functional outcomes associated with a given form. To date, the best defined models are those of HH6 limbic encephalitis in posttransplant patients and progressive multifocal leukoencephalopathy (PML) in HIV infection and treatment with monoclonal antibodies, having a very different prognosis in the two settings.
7.1.4 Antiviral Therapies
The antiviral and antiretroviral treatments introduced over the past two decades have changed the natural course of certain forms of encephalitis, in particular, herpes simplex encephalitis and all the HIV-related complications. Estimated survival rates have increased significantly, and the frequency of medium- to-long-term complications has fallen. Unfortunately, however, there still exist many forms of encephalitis for which there is no etiological treatment and whose outcome is determined essentially by variables related to the host and by the symptomatic treatment.
7.2 Herpesviruses
Herpesviruses are a common cause for severe acute and chronic neurological disease of the central nervous system (CNS), either during primary infection or following reactivation from a latent state. Especially in the immunosuppressed, the infection can take a life-threatening course, and diagnosis can be challenging, due to the presence of atypical clinical and instrumental findings [6]. Therefore, the early detection of herpesvirus-associated neurological diseases should have high priority.
In immunocompromised hosts, in whom herpesviruses can undergo systemic reactivation, it is of capital importance to perform PCR CSF/serum ratio to distinguish active CNS compartmental viral replication from systemic responses.In this chapter, we will consider the neurological diseases caused by six neurotropic herpesviruses: herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HH6).
7.3 Herpes Simplex
Key Facts
Terminology and definition – Species: Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2); genus: Simplex virus; family: Herpesviridae.
Epidemiology – HSE is the most common form of sporadic viral encephalitis in the general population. HSVs infect via mucosal surfaces or damaged skin. Primary infection with HSV-1 usually occurs during childhood or adolescence, and is asymptomatic or results in gengivostomatitis. After primary infection, HSV-1 establishes latency in the neurons of the trigeminal ganglion, and can undergo reactivation with oral mucocutaneous shedding.
Clinical features – The most frequent clinical features include fever, headache, aphasia, seizures, and alterations of consciousness, personality, and behavior, mimicking acute psychiatric conditions.
HSV-2 can also be responsible for a form of benign, recurrent, lymphocytic meningitis (Mollaret’s meningitis).
Diagnostic markers
CSF – inflammatory changes in >95 % of cases.
PCR for HSV-1 DNA – very sensitive (98 %) and specific (94 %).
HSV CSF/serum antibody ratio may be helpful if > 1 week into therapy.
Imaging – Monolateral or bilateral temporoinsular hyperintensity (MR-FLAIR and T2W images); hemorrhagic foci.
Prognosis – Neurologic sequelae in surviving patients are often severe, including focal deficits, seizures, and neuropsychological changes. Untreated, mortality approaches 70%.
Principles of treatment – Intravenous acyclovir 10 mg/kg every 8 h for 14–21 days. Early recognition of the infection is critical since a delay in therapy is associated with increased morbidity and mortality. In the immunocompromised, HSV resistance to acyclovir is a serious concern, affecting about 5–25% of patients receiving long-term antiviral prophylaxis.
7.3.1 Prognosis
7.3.1.1 Mortality and Disability
Although the prognosis for patients with HSE has been dramatically improved by the availability of specific antiviral therapy, neurologic sequelae in surviving patients are often severe, including focal deficits, seizures, and neuropsychological changes. If untreated, mortality approaches 70 %.
The table below summarizes the prognostic factors for HSE.
Prognostic factors (predictors of poor outcome) |
|---|
Older age |
Depressed level of consciousness before the onset of therapy |
Delay of >2 days between admission to the hospital and initiation of acyclovir |
Simplified Acute Physiology Score II ≥27 at admission |
Disorientation |
Low albumin levels |
Low sodium levels |
Abnormal early CT scan |
Immunocompetent Hosts
In immunocompetent hosts, HSE mortality is estimated between 10 and 25 %, despite adequate treatment; about half of the deaths are attributable directly to encephalitis and another half to infectious complications.
Among survivors, the overall incidence of neurologic sequelae is 30–70 %, ranging from mild/moderate (20–50 %) to severe (10–20 %) [7, 8]. The most common long-term sequelae are represented by memory impairment (69 %), anosmia (65 %), personality and behavioral changes (45 %), dysphasia (41 %), and epilepsy (24 %) [7]. The severity of the amnesia appears to correlate with the presence of bilateral medial limbic (hippocampal) damage and with its severity, detected by MRI.
Overall, only 14–48 % of the patients regain a premorbid level of functioning.
About 87 % of the survivors are eventually readmitted to the hospital due to epilepsy, infections (other than HSE), or neuropsychiatric conditions [9].
Immunocompromised Hosts
Although HSE is most commonly seen in immunocompetent hosts, cases of HSE in the context of immunosuppression such as HIV infection, cancer, solid organ or bone marrow transplantation have now been reported. In this setting, HSE presents with atypical clinical and instrumental findings, making diagnosis of the condition particularly challenging. This may possibly contribute to the high morbidity and mortality observed in this cohort [6].
Cancer HSE has been reported in individual patients with cancer, with a majority of cases occurring shortly after brain irradiation. Additional sources of immunosuppression include chemotherapies and corticosteroids. However, estimates of the incidence of HSE in people with cancer compared to the general population are not available. | ||||
References | No of cases | Mortality | Residual Disability | |
Graber, 2011 [10] | 31 | 20 (65 %) | Not available | |
HIV infection Most cases of HSE in HIV-infected patients date back to the pre-HAARTa era, occurring in association to CMV encephalitis. In this setting, mortality was extremely high, and diagnosis mainly autoptic. Latest reports indicate a mortality of about one-quarter or less, comparable to that of the general population. | ||||
Solid organ transplantation In solid organ transplant recipients, HSV-systemic reactivation may be seen in the first post-transplant month, in the absence of prophylaxis. Still, HSE rarely occurs; only a few cases after renal transplantation are reported in literature. | ||||
Bone marrow transplantation Up to 25 % of patients who undergo allogenic stem cell transplantation suffer from severe neurological complications involving the CNS, frequently infections, which are associated with a poor outcome. The leading causative organisms of CNS infections in patients with malignancies are Toxoplasma gondii and fungi; viral infections have less frequently been reported. | ||||
References | No of cases | Mortality | Residual Disability | |
Schmidt-Hieber, 2011 [11] | 4 | 1 (25 %) | 1 (25 %) | |
Wu, 2013 [12] | 5 | 3 (60 %) | 1 (20 %) | |
Monoclonal antibodies HSE has rarely been reported in patients receiving monoclonal antibodies for rheumatologic disorders or multiple sclerosis. In this setting, HSE retains a relatively good prognosis. | ||||
References | No of cases | Mortality | Residual Disability | |
TNF-α inhibitors (rheumatologic disorders) | Bradford, 2009 [13] | 3 | 0 | 2 (67 %) |
Natalizumab (multiple sclerosis) | Fine, 2013 [14] | 11 | 2 (18 %) | 3 (27 %) |
7.4 Varicella Zoster
Key Facts
Terminology and definitions – Species: Varicella zoster virus (VZV) or Human herpesvirus 3 (HHV-3); genus: Varicellovirus; family: Herpesviridae.
Epidemiology – Primary infection results in varicella (syn.: chicken pox). Viral transmission occurs by direct contact with skin lesions or by respiratory aerosols from infected individuals. After varicella resolves, VZV becomes latent in the peripheral nervous system and persists throughout the lifetime of the host.
Clinical features – Neurological complications caused by VZV can occur either during primary infection or following reactivation, and can be caused by direct viral invasion or by vasculitis. They all can course with or without cutaneous rash.
Acute cerebellar ataxia 1/4000 children with varicella, with headache, vomiting, and mild cerebellar dysfunction.
Encephalitis without vasculopathy can affect both immunocompetent and immunosuppressed patients with nonspecific clinical features.
Large vessel unifocal granulomatous arteritis usually affects immunocompetent elderly individuals; the typical presentation is headache and hemiplegia occurring in patients with a recent history of herpes zoster ophthalmicus.
Small vessel multifocal vasculopathy usually occurs in severely immunocompromised patients (AIDS, lymphoproliferative disorders) and consists of subacute multifocal neurological deficits accompanied by headache, fever, mental changes, and seizures.
Postzoster myelitis: Sensory–motor dysfunction in the same spinal cord segment as in the cutaneous rash. Immunocompromised patients are at increased risk, and the syndrome is well-described in patients with AIDS.
Diagnostic markers
CSF: moderate inflammatory changes.
PCR for VZV in acute cerebellar ataxia, encephalitis, and vasculopathies.
VZV CSF/serum antibody ratio is significantly altered in vasculopathies.
Imaging – MR usually normal (acute cerebellar ataxia); normal or n.s. supra- or infratentorial T2 hyperintensities in white/gray matter (encephalitis); ischemic infarction with focal stenosis or occlusion of the affected vessel (large vessel arteritis); multifocal brain infarcts (small vessel multifocal vasculopathy).
Prognosis – Potentially lethal in both immunocompetente and immunocompromised patients.
7.4.1 Prognosis
7.4.1.1 Principles of Treatment
Therapy of VZV neurological complications has to rely on the context of immunocompetence, the possible putative pathogenesis, and disease severity.
In the context of immunosuppression, therapy with intravenous acyclovir is always recommended.
7.4.1.2 Mortality and Disability
Varicella zoster reactivation in the CNS is associated with a variety of serious and potentially lethal complications in both immunocompetent and immunocompromised individuals. Prognosis depends on age, immunological status of the host, and clinical pattern [15, 16].
Acute cerebellar ataxia Cerebellar ataxia associated with varicella is self-limited and has a favorable prognosis. Mortality is essentially zero, and deaths that occur are usually attributed to the development of nonneurologic complications. Still, a significant number of patients experience residual disability. | |||
References | No of cases | Mortality | Residual disability |
Connolly, 1994 [17] | 26 | 0 % | Behavioral abnormalities (31 %); speech abnormalities (19 %) |
Camacho-Badilla, 2008 [18] | 37 | 0 % | Minor sequelae (54 %) |
Encephalitis | |||
During the last decades, the mortality for VZV encephalitis has ranged from 5 to 35 %. The actual mortality rate is probably around 10–15 %, with good recovery expected in most cases. | |||
References | No of cases | Mortality | Residual disability |
De Broucker, 2012 [19] | 20 | 3 (15 %) | Moderate to severe sequelae (41 %): cognitive impairment, sensory–motor deficits, ataxia |
Large vessel unifocal granulomatous arteritis The mortality rate is 20–25 %, with a high incidence of permanent neurologic sequelae among survivors (headache, focal deficits, coma). | |||
Small vessel multifocal vasculopathy Prognosis is usually unfavorable, characterized by high short-term mortality. | |||
Myelitis In immunocompetent hosts, the involvement of the spinal cord is subtle and usually followed by complete recovery. Conversely, in immunocompromised individuals, the infection is often severe, leading to partial or total cord transection with substantial neurologic sequelae, or even death. | |||
7.4.1.3 VZV Neurologic Disease in Settings of Immunosuppression
HIV/AIDS patients The larger series reports 34 cases of neurological complications due to VZV [20], including encephalitis (13 cases), myelitis (8 cases), radiculitis (7 cases), and meningitis (6 cases). Neurological manifestations often involved simultaneously several sites in the central and/or peripheral nervous system. Severe symptoms at onset and a lower CD4 cell count were associated with poorer outcome. | |||
References | No of cases | Mortality | Residual disability |
De La Blanchardiere, 2000 [20] | 34 | 6 (18 %) | Severe sequelae (29 %), complete recovery (53 %) |
Bone marrow transplantation Although VZV reactivation during the first 24 months from bone marrow transplantation is a common event, VZV meningoencephalitis is a rare complication, often occurring after the suspension of antiviral prophylaxis. Few cases are reported in literature, some with fatal outcome. | |||
References | No of cases | Mortality | Residual disability |
Suzuki, 2012 [21] | 1 + 12 | 2 (15 %) | Not available |
Monoclonal antibodies | |||
7.5 Epstein–Barr
Key Facts
Terminology and definitions – Species: Epstein–Barr virus (EBV); genus: Lymphocryptovirus; family: Herpesviridae.
Epidemiology – EBV is one of the most widespread viruses, infecting over 90 % of human beings in the first decades of life. EBV is most frequently transmitted via saliva. Primary infection is asymptomatic or results in infectious mononucleosis; once the initial lytic infection is brought under control, EBV establishes latency in B cells.
Clinical features – Complications caused by EBV can involve the central or peripheral nervous system and can occur shortly before, during, or after infectious mononucleosis, as well as following acute EBV infection in the absence of symptomatic mononucleosis.
Aseptic meningitis is the most common complication of primary EBV infection.
Encephalitis is characterized by nonspecific clinical features ranging from fever and headache, to seizures, personality changes, and coma.
Myelitis may sometimes accompany encephalitis.
EBV has also been associated with AIDS-related CNS lymphomas and posttransplant lymphoproliferative disorders (PTLD). These entities range from reversible lymphoproliferative disorders that recover with the suspension of immunosuppressants, to malignant aggressive lymphomas.
Diagnostic markers
CSF: lymphocytic pleocytosis and mild elevation in protein levels.
The value of PCR assessment for EBV infections is uncertain, as EBV DNA is often detected in the CSF in the absence of neurological symptoms.
Imaging: T2W hyperintensities in cerebral white and/or gray matter on MRI.
Prognosis – Aseptic meningitis has self-limiting course. Enchefalitis has 10-20% mortality rate.
7.5.1 Prognosis
7.5.1.1 Principles of Treatment
No specific antiviral therapy is available for the treatment of EBV-related neurologic complications, and therapy is mainly supportive. Corticosteroids may be effective in selected cases.
7.5.1.2 Mortality and Disability
Aseptic meningitis: Self-limiting course; usually resolves without neurologic sequelae.
Encephalitis: Mortality of 10–20 %. Incidence of neurologic sequelae of 20–38 % in immunocompetent hosts.
Most cases of myelitis occur in children and young adults, and eventually resolve without sequelae, although reports of long-term sensory–motor deficits exist.
7.6 Cytomegalovirus
Key Facts
Terminology and definitions – Species: Human cytomegalovirus (CMV); genus: Cytomegalovirus; family: Herpesviridae.
Epidemiology – Primary infection with CMV usually occurs early in life by direct contact with bodily fluids (saliva, urine, blood, vaginal secretions, or semen) and is asymptomatic or can manifest as infectious mononucleosis. After primary infection, the virus establishes latency and is able to undergo reactivation in the event of immunosuppression.
Clinical features – CMV encephalitis usually presents with nonspecific signs of encephalopathy, such as lethargy, confusion, and seizures. Immunocompromised individuals are at increased risk for potentially fatal disseminated CMV infections that can involve the eye, cochlea, and the CNS. Rarely, CMV can induce myelitis or polymononeuritis.
Diagnostic markers
CSF analysis and PCR for CMV.Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
