Herpes Simplex Virus Encephalitis in Patients With Autoimmune Conditions or Exposure to Immunomodulatory Medications.

BACKGROUND AND OBJECTIVES: Among infectious etiologies of encephalitis, herpes simplex virus type 1 (HSV-1) is most common, accounting for ∼15%-40% of adult encephalitis diagnoses. We aim to investigate the association between immune status and HSV encephalitis (HSVE). Using a US Medicaid database of 75.6 million persons, we evaluated the association between HSVE and autoimmune conditions, exposure to immunosuppressive and immunomodulatory medications, and other medical comorbidities. METHODS: We used the US Medicaid Analytic eXtract data between 2007 and 2010 from the 29 most populated American states. We first examined the crude incidence of HSVE in the population. We then age and sex-matched adult cases of HSVE with a sufficient enrollment period (12 months before HSVE diagnosis) to a larger control population without HSVE. In a case-control analysis, we examined the association between HSVE and exposure to both autoimmune disease and immunosuppressive/immunomodulatory medications. Analyses were conducted with conditional logistic regression progressively adjusting for sociodemographic factors, Charlson Comorbidity Index, and non-autoimmune comorbidities. RESULTS: Incidence of HSVE was ∼3.01 per 105 person-years among adults. A total of 951 HSVE cases and 95,100 age and sex-matched controls were compared. The HSVE population had higher rates of medical comorbidities than the control population. The association of HSVE and autoimmune conditions was strong (adjusted odds ratio (OR) 2.6; 95% CI 2.2-3.2). The association of HSVE and immunomodulating medications had an OR of 2.2 (CI 1.9-2.6), also after covariate adjustment. When both exposures were included in regression models, the associations remained robust: OR 2.3 (CI 1.9-2.7) for autoimmune disease and 2.0 (CI 1.7-2.3) for immunosuppressive and immunomodulatory medications. DISCUSSION: In a large, national population, HSVE is strongly associated with preexisting autoimmune disease and exposure to immunosuppressive and immunomodulatory medications. The role of antecedent immune-related dysregulation may have been underestimated to date.

Revisiting a Telencephalic Extent of the Ascending Reticular Activating System.

Is the cerebrum involved in its own activation to states of attention or arousal? "Telencephalon" is a term borrowed from embryology to identify not only the cerebral hemispheres of the forebrain, but also the basal forebrain. We review a generally undercited literature that describes nucleus basalis of Meynert, located within the substantia innominata of the ventrobasal forebrain, as a telencephalic extension of the ascending reticular activating formation. Although that formation's precise anatomical definition and localization have proven elusive over more than 70 years, a careful reading of sources reveals that there are histological features common to certain brainstem neurons and those of the nucleus basalis, and that a largely common dendritic architecture may be a morphological aspect that helps to define non-telencephalic structures of the ascending reticular activating formation (e.g., in brainstem) as well as those parts of the formation that are telencephalic and themselves responsible for cortical activation. We draw attention to a pattern of dendritic arborization described as "isodendritic," a uniform (isos-) branching in which distal dendrite branches are significantly longer than proximal ones. Isodendritic neurons also differ from other morphological types based on their heterogeneous, rather than specific afferentation. References reviewed here are consistent in their descriptions of histology, particularly in studies of locales rich in cholinergic neurons. We discuss the therapeutic implications of a basal forebrain site that may activate cortex. Interventions that specifically target nucleus basalis and, especially, the survival of its constituent neurons may benefit afflictions in which higher cortical function is compromised due to disturbed arousal or attentiveness, including not only coma and related syndromes, but also conditions colloquially described as states of cognitive "fog" or of "long-haul" mental compromise.

Review: Subjective Time Perception, Dopamine Signaling, and Parkinsonian Slowness.

The association between idiopathic Parkinson's disease, a paradigmatic dopamine-deficiency syndrome, and problems in the estimation of time has been studied experimentally for decades. I review that literature, which raises a question about whether and if dopamine deficiency relates not only to the motor slowness that is an objective and cardinal parkinsonian sign, but also to a compromised neural substrate for time perception. Why does a clinically (motorically) significant deficiency in dopamine play a role in the subjective perception of time's passage? After a discussion of a classical conception of basal ganglionic control of movement under the influence of dopamine, I describe recent work in healthy mice using optogenetics; the methodology visualizes dopaminergic neuronal firing in very short time intervals, then allows for correlation with motor behaviors in trained tasks. Moment-to-moment neuronal activity is both highly dynamic and variable, as assessed by photometry of genetically defined dopaminergic neurons. I use those animal data as context to review a large experimental experience in humans, spanning decades, that has examined subjective time perception mainly in Parkinson's disease, but also in other movement disorders. Although the human data are mixed in their findings, I argue that loss of dynamic variability in dopaminergic neuronal activity over very short intervals may be a fundamental sensory aspect in the pathophysiology of parkinsonism. An important implication is that therapeutic response in Parkinson's disease needs to be understood in terms of short-term alterations in dynamic neuronal firing, as has already been examined in novel ways-for example, in the study of real-time changes in neuronal network oscillations across very short time intervals. A finer analysis of a treatment's network effects might aid in any effort to augment clinical response to either medications or functional neurosurgical interventions in Parkinson's disease.

Dysarthria-Facial Paresis and Rostral Pontine Ischemic Stroke.

We describe an acute, postoperative dysarthria-facial paresis. While the rare stroke syndrome has been described previously, we present an under-described clinical nuance to its presentation with a particularly clear imaging correlation. A 78-year-old, right-handed man with a past medical history of aortic stenosis presented after a transcatheter aortic valve replacement. Immediately postoperatively, no neurological deficits were noted. That evening, he described his speech as "drunken." He was later noted to have a right lower facial droop in addition to the speech change. His speech exhibited labial, lingual, and (to a lesser degree) guttural dysarthria. At the patient's request due to claustrophobia, he received 2 mg of oral lorazepam prior to cranial imaging. Afterwards, he was sleepy but arousable, yet was unable to put pen to paper when asked to write. Right lower facial paresis persisted, but he now demonstrated a right pronator drift, which resolved after 14 h without other evolution to his clinical examination. Brainstem lesions above the level of the pontine facial nucleus may present with central facial paresis contralateral to the lesion. An associated dysarthria may have both labial and lingual features in the absence of tongue or pharyngeal weakness. Our review of reported cases of dysarthria in isolation, dysarthria in combination with facial paresis, and facial paresis finds that all presentations may result from cortical, subcortical, or brainstem involvement. Stroke mechanisms are most commonly thromboembolic or small-vessel-ischemic in either the anterior or posterior circulations.

Imaging features, therapies, and outcomes of fibrosing inflammatory pseudotumor of the nasopharynx: A systematic review.

BACKGROUND AND PURPOSE: Fibrosing inflammatory pseudotumor (FIP) of the nasopharynx is a rare nonneoplastic inflammatory lesion that is frequently mistaken for malignancy or infection. It is often misdiagnosed by radiologists as nasopharyngeal carcinoma or lymphoma, resulting in multiple biopsies and delays in diagnosis. The purpose is to understand trends in clinical presentation, imaging findings, treatment modalities, and patient outcomes of nasopharyngeal FIP. METHODS: MEDLINE and EMBASE databases were queried for articles related to FIP of the nasopharynx. Articles that described cases of FIP involving the nasopharynx were selected. Studies that described inflammatory pseudotumor of the nasopharynx associated with known distinct pathologic entities were excluded. RESULTS: A total of 19 articles describing 37 patients were included. MRI findings were reported in 32 patients. All cases demonstrated avid gadolinium enhancement. T2-weighted imaging characteristics were described or displayed for 21 patients: 95% demonstrated hypointensity compared to surrounding mucosa. Fluorodeoxyglucose (FDG) PET/CT findings were reported for 6 patients, all demonstrating mild FDG avidity. CONCLUSIONS: Nasopharyngeal FIP is a histological diagnosis of exclusion that presents with facial pain and, often, cranial neuropathies. Relatively low T2-weighted MRI signal should inform the interpreting neuroradiologist to include FIP as a differential consideration for both the ordering provider and pathologist. Corticosteroid therapy is the most frequently employed therapy and results in partial or complete response in most patients. Radiation therapy and anti-inflammatory medications have also been reported to have potential therapeutic roles.

The phenomenon of clasmatodendrosis.

Clasmatodendrosis derives from the Greek for fragment (klasma), tree (dendron), and condition (- osis). Cajal first used the term in 1913: he observed disintegration of the distal cell processes of astrocytes, along with a fragmentation or beading of proximal processes closer to the astrocyte cell body. In contemporary clinical and experimental reports, clasmatodendrosis has been observed in models of cerebral ischemia and seizures (including status epilepticus), in elderly brains, in white matter disease, in hippocampal models and cell cultures associated with amyloid plaques, in head trauma, toxic exposures, demyelinating diseases, encephalitides and infection-associated encephalopathies, and in the treatment of cancer using immune effector cells. We examine evidence to support a claim that clasmatodendrotic astrocyte cell processes overtly bead (truncate) as a morphological sign of ongoing damage premortem. In grey and white matter and often in relationship to vascular lumina, beading becomes apparent with immunohistochemical staining of glial fibrillary acidic protein when specimens are examined at reasonably high magnification, but demonstration of distal astrocytic loss of processes may require additional marker study and imaging. Proposed mechanisms for clasmatodendrotic change have examined hypoxic-ischemic, osmotic-demyelinating, and autophagic models. In these models as well as in neuropathological reports, parenchymal swelling, vessel-wall leakage, or disturbed clearance of toxins can occur in association with clasmatodendrosis. Clasmatodendrotic features may serve as a marker for gliovascular dysregulation either acutely or chronically. We review correlative evidence for blood-brain barrier (BBB) dysfunction associated with astrocytic structural change, with attention to interactions between endothelial cells, pericytes, and astrocytic endfeet.

Fibrosing Inflammatory Pseudotumor Presenting as Cranial Neuropathy.

We report two cases of biopsy-corroborated "fibrosing inflammatory pseudotumor" to illustrate that the entity, rarely described in the neurological literature, should be included in the differential diagnosis of either a cranial mononeuropathy or, certainly, in the case of progressive cranial neuropathies. A broad differential diagnosis arises in certain contexts. Early steroid treatment can be effective, and perhaps later-generation immune-modulating agents may confer further options, although there is no known definitive treatment.