Michael J. Bradshaw

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be life-saving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.

The Inflammatory Form of Cerebral Amyloid Angiopathy or “Cerebral Amyloid Angiopathy-Related Inflammation” (CAARI)

Cerebral amyloid angiopathy-related inflammation (CAARI) is a recently recognized syndrome of reversible encephalopathy seen in a subset of patients with cerebral amyloid angiopathy (CAA). CAA is a disorder of the elderly in which amyloid peptides are deposited in the walls of cerebral arteries, leading to microhemorrhages, macrohemorrhages, and eventually dementia. In a few cases, the amyloid deposition is accompanied by inflammation or edema. The clinical syndrome of CAARI is distinguished by subacute neurobehavioral symptoms, headaches, seizures, and stroke-like signs, contrasting the acute intracranial hemorrhage typically seen in CAA. Magnetic resonance imaging findings may be symmetric or asymmetric and involve patchy or confluent T2 hyperintense lesions in the cortex and subcortical white matter. Recent diagnostic criteria have been proposed which help distinguish CAARI from alternative diagnoses. Improvement has been reported in most cases with immunosuppression, although a few cases have had recurrent symptoms. Here, we review the clinical and radiologic features of CAARI and compare these with CAA.

Infliximab for the treatment of CNS sarcoidosis: A multi-institutional series

Objective: To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor–α. Methods: Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis following rigorous exclusion of other causes. Results: Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24–71 years); 56.1% were female; 62.1% were white, 37.0% African American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4–8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n = 56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location. Conclusions: Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments. Classification of evidence: This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses.

Herpes simplex virus 1 encephalitis associated with voltage-gated calcium channel autoimmunity

Encephalitis is a significant cause of morbidity and mortality, yet a causative factor is identified in <50% of cases.1 The most common causes are infectious (particularly herpes simplex virus [HSV]) and autoimmune.2 Diagnosis of the latter potentially treatable cause is aided by the detection in serum or CSF of an informative profile of autoantibodies against neuronal intracellular proteins and plasma membrane proteins (e.g., voltage-gated potassium channel [VGKC] complex and calcium channels [VGCC, P/Q-type or N-type] and a growing list of glutamate receptors [R] and other autoantibodies of synaptic specificity).3,4 Neural autoantibodies, particularly NMDA-R-IgG, have recently been reported in the setting of viral encephalitides.5,6 Herein, we report a unique case of N-type VGCC autoantibody temporally associated with HSV encephalitis.

Autopsy-proven demyelination associated with infliximab treatment

Tumor necrosis factor–α (TNF-α) is a well-studied proinflammatory cytokine that contributes to the pathogenesis of immune and infectious diseases. TNF-α effects are mediated by signaling through TNF-α receptors, which are present ubiquitously.1 Limiting the actions of TNF-α, either by blocking the receptor or inhibiting circulating (free) TNF-α, is a useful treatment strategy in autoimmune disorders with prominent inflammation, such as inflammatory bowel disease and rheumatoid arthritis (RA). However, when treatment with agents that inhibit TNF-α function was applied to multiple sclerosis (MS), an unanticipated worsening was observed. The clinical trial of lenercept (a recombinant TNF-α receptor–immunoglobulin 1g fusion protein that protected against experimental autoimmune encephalitis) for the treatment of relapsing-remitting multiple sclerosis was stopped prematurely when the treatment arm was noted to have earlier and more frequent exacerbations.2 TNF-α antagonists are therefore contraindicated in patients with MS. In patients with no history of demyelinating disease, TNF-α antagonism has led to unmasking of demyelinating events with a clinical pattern typical of that seen in MS.3 All CNS cases of demyelinating disease to date have been based on clinical, laboratory, and radiographic findings. Herein we present a unique case of histologically confirmed demyelination following treatment with TNFα inhibitors.

Wearable biosensors to monitor disability in multiple sclerosis

Purpose of review Biosensors capable of measuring physiologic and kinetic parameters associated with disability are being applied to the study of people with multiple sclerosis (MS). We review the use of biosensors in people with MS with an emphasis on measuring/monitoring disability and understanding knowledge gaps between biosensor data and clinical care. Recent findings Accelerometers are available to the public and may be able to help the clinician understand a patients degree of disability. Further studies with wearable biosensors capable of measuring other physiologic features, such as vital signs, are needed and are likely to contribute to our understanding of MS. Summary Wearable biosensors can improve our understanding of disability, response to treatment, and natural history of MS.

Child Neurology: Neuromyelitis optica spectrum disorders

A 3-year-old girl presented with 4 days of progressive bilateral vision loss. Medical history included presumed autoimmune hepatitis at 6 months of age, when she had an extensive evaluation including hepatitis A immunoglobulin G (IgG) detected in her serum, thought to represent maternal antibodies. Liver biopsy suggested autoimmune hepatitis and she was treated with oral prednisolone 2 mg daily for 2 weeks and remained on maintenance 1 mg daily. Family and social histories were unremarkable.

Child Neurology: Rocky Mountain spotted fever encephalitis

A 27-month-old previously healthy boy developed irritability and a fever the day after getting his 2-year vaccinations. Three days later, he developed a centripetally spreading petechial rash. A tick was removed from his neck. He was taken to an outside hospital several times over the course of 3–4 days and was discharged with amoxicillin the first time and ceftriaxone on a subsequent visit. Eight days into his illness, he developed depressed level of consciousness and had what was described as a generalized clonic seizure. He was intubated with paralytics and fentanyl and transferred to our hospital for evaluation and management. The remaining history was unremarkable.

Clinical Reasoning: A 52-year-old man with diplopia and ataxia

A 52-year-old man presented with a month of progressive, painful, right-sided spasms, dysarthria, horizontal diplopia, left facial droop, and headaches. Over the last year, he had developed progressive gait ataxia that required use of a walker.

An Overview of Autoimmune and Paraneoplastic Encephalitides

Abstract The understanding of the manifestations, mechanisms, and management of autoimmune encephalitis has expanded dramatically in recent decades. Immune‐mediated encephalitides are comparable in incidence and prevalence to infectious etiologies, and are associated with significant morbidity, especially when there is a delay in recognition and treatment. As such, clinicians from many specialties must develop a functional understanding of these disorders. Herein we provide an overview of the autoimmune and paraneoplastic encephalitides, including those associated with either intracellular or cell surface/synaptic neuronal autoantibodies. After briefly reviewing the current understanding of the pathobiology of autoimmune encephalitis, we combine a neuroanatomical approach with specific antibody syndromes to provide the reader with a clinically relevant review of these disorders. The clinical manifestations, diagnosis, and management of autoimmune encephalitis are reviewed, with an emphasis on clinical relevance. We also introduce updates in the field, including autoimmune encephalitis associated with novel cancer immunotherapies, infectious triggers of autoimmune encephalitis, and autoimmune encephalitis with demyelinating overlap syndromes.