Sashank Prasad

Network localization of neurological symptoms from focal brain lesions

A traditional and widely used approach for linking neurological symptoms to specific brain regions involves identifying overlap in lesion location across patients with similar symptoms, termed lesion mapping. This approach is powerful and broadly applicable, but has limitations when symptoms do not localize to a single region or stem from dysfunction in regions connected to the lesion site rather than the site itself. A newer approach sensitive to such network effects involves functional neuroimaging of patients, but this requires specialized brain scans beyond routine clinical data, making it less versatile and difficult to apply when symptoms are rare or transient. In this article we show that the traditional approach to lesion mapping can be expanded to incorporate network effects into symptom localization without the need for specialized neuroimaging of patients. Our approach involves three steps: (i) transferring the three-dimensional volume of a brain lesion onto a reference brain; (ii) assessing the intrinsic functional connectivity of the lesion volume with the rest of the brain using normative connectome data; and (iii) overlapping lesion-associated networks to identify regions common to a clinical syndrome. We first tested our approach in peduncular hallucinosis, a syndrome of visual hallucinations following subcortical lesions long hypothesized to be due to network effects on extrastriate visual cortex. While the lesions themselves were heterogeneously distributed with little overlap in lesion location, 22 of 23 lesions were negatively correlated with extrastriate visual cortex. This network overlap was specific compared to other subcortical lesions (P < 10(-5)) and relative to other cortical regions (P < 0.01). Next, we tested for generalizability of our technique by applying it to three additional lesion syndromes: central post-stroke pain, auditory hallucinosis, and subcortical aphasia. In each syndrome, heterogeneous lesions that themselves had little overlap showed significant network overlap in cortical areas previously implicated in symptom expression (P < 10(-4)). These results suggest that (i) heterogeneous lesions producing similar symptoms share functional connectivity to specific brain regions involved in symptom expression; and (ii) publically available human connectome data can be used to incorporate these network effects into traditional lesion mapping approaches. Because the current technique requires no specialized imaging of patients it may prove a versatile and broadly applicable approach for localizing neurological symptoms in the setting of brain lesions.

Isolated Third, Fourth and Sixth Cranial Nerve Palsies From Presumed Microvascular Versus Other Causes: A Prospective Study

PURPOSE To estimate the proportion of patients presenting with isolated third, fourth, or sixth cranial nerve palsy of presumed microvascular origin versus other causes. DESIGN Prospective, multicenter, observational case series. PARTICIPANTS A total of 109 patients aged 50 years or older with acute isolated ocular motor nerve palsy. TESTING Magnetic resonance imaging (MRI) of the brain. MAIN OUTCOME MEASURES Causes of acute isolated ocular motor nerve palsy (presumed microvascular or other) as determined with early MRI and clinical assessment. RESULTS Among 109 patients enrolled in the study, 22 had cranial nerve III palsy, 25 had cranial nerve IV palsy, and 62 had cranial nerve VI palsy. A cause other than presumed microvascular ischemia was identified in 18 patients (16.5%; 95% confidence interval, 10.7-24.6). The presence of 1 or more vasculopathic risk factors (diabetes, hypertension, hypercholesterolemia, coronary artery disease, myocardial infarction, stroke, and smoking) was significantly associated with a presumed microvascular cause (P = 0.003, Fisher exact test). Vasculopathic risk factors were also present in 61% of patients (11/18) with other causes. In the group of patients who had vasculopathic risk factors only, with no other significant medical condition, 10% of patients (8/80) were found to have other causes, including midbrain infarction, neoplasms, inflammation, pituitary apoplexy, and giant cell arteritis (GCA). By excluding patients with third cranial nerve palsies and those with GCA, the incidence of other causes for isolated fourth and sixth cranial nerve palsies was 4.7% (3/64). CONCLUSIONS In our series of patients with acute isolated ocular motor nerve palsies, a substantial proportion of patients had other causes, including neoplasm, GCA, and brain stem infarction. Brain MRI and laboratory workup have a role in the initial evaluation of older patients with isolated acute ocular motor nerve palsies regardless of whether vascular risk factors are present.

Trigeminal neuralgia: historical notes and current concepts.

Background:Trigeminal neuralgia is a syndrome of paroxysmal excruciating, lancinating unilateral facial pain. Review Summary:There are several clinical features that are characteristic of trigeminal neuralgia, but there may be red flags that should suggest alternative diagnoses. There is convincing evidence that the idiopathic form develops from focal demyelination at the trigeminal root entry zone with subsequent ephaptic cross-talk between axons. Vascular compression of the nerve root causes this demyelination in most patients. Medical management of this condition, using anticonvulsant therapy and other agents, aims to dampen the abnormal electrical signals and to ameliorate symptoms. In refractory cases, a number of surgical interventions can be considered, the most common of which is microvascular decompression of the trigeminal nerve. Gamma knife therapy is emerging as an alternative treatment for the patient with medically refractive trigeminal neuralgia, particularly in the elderly patient with comorbid conditions. Conclusion:Knowledge of the proper diagnosis and management of trigeminal neuralgia is essential to the successful management of these patients.

Ipilimumab-induced Ocular and Orbital Inflammation—A Case Series and Review of the Literature

Abstract Purpose: Ipilimumab, a monoclonal antibody directed against the immune protein cytotoxic T-lymphocyte antigen-4 (CTLA-4), characteristically induces side effects called “immune-related adverse events” (IRAE). Although ophthalmic involvement is rare, we report 7 cases of eye and orbit complications related to ipilimumab therapy. Methods: We performed a retrospective review of patients with metastatic melanoma who developed ipilimumab-related ocular or orbital inflammation who were seen at our institutions. Results: Seven patients were identified: 4 patients had orbital inflammation, 2 had uveitis, and 1 had peripheral ulcerative keratitis. Four patients developed inflammation after the second ipilimumab infusion, 2 after the third infusion and 1 after the first infusion. All 4 patients with orbital inflammation were treated with systemic corticosteroids. Two patients with uveitis were treated with topical steroids, but were also treated with systemic corticosteroids for other IRAE, including colitis and hypophysitis. The patient with keratitis was treated with topical corticosteroids alone with resolution of inflammation. All 7 patients discontinued ipilimumab therapy, 5 due to systemic IRAE and 2 due to tumor progression. Five of 7 patients had tumor progression on ipilimumab therapy. Conclusions: Ocular and orbital inflammation may occur in patients with metastatic melanoma receiving ipilimumab, is frequently accompanied by other IRAEs, and resolves with corticosteroid treatment, often leaving no long-term sequelae.

Eye Movement Abnormalities in Multiple Sclerosis

Patients with multiple sclerosis commonly describe visual symptoms that result from several eye movement abnormalities that occur from disruption of critical pathways in the brainstem, cerebellum, and cerebral hemispheres. These abnormalities include internuclear ophthalmoplegia, ocular motor palsy, ocular misalignment, pathologic nystagmus, impaired saccades, saccadic intrusions, and impaired pursuit. Detailed knowledge of these problems and their neuroanatomic localization will aid the physician by guiding diagnosis and therapeutic decision making.

Neural activity within area v1 reflects unconscious visual performance in a case of blindsight

Although lesions of the striate (V1) cortex disrupt conscious vision, patients can demonstrate surprising residual abilities within their affected visual field, a phenomenon termed blindsight. The relative contribution of spared islands of functioning striate cortex to residual vision, versus subcortical pathways to extrastriate areas, has implications for the role of early visual areas in visual awareness and performance. Here we describe the behavioral and neural features of residual cortical function in Patient M.C., who sustained a posterior cerebral artery stroke at the age of 15 years. Within her impaired visual field, we found preserved visual abilities characteristic of blindsight, including superior detection of motion, and above-chance discrimination of shape, color, and motion direction. Functional magnetic resonance imaging demonstrated a retinotopically organized representation of M.C.s blind visual field within the lesioned occipital lobe, specifically within area V1. The incongruity of a well-organized cortex and M.C.s markedly impaired vision was resolved by measurement of functional responses within her damaged occipital lobe. Attenuated neural contrast-response functions were found to correlate with M.C.s impaired psychophysical performance. These results demonstrate that the behavioral features of blindsight may arise in the presence of residual striate responses that are spatially organized and sensitive to contrast variation.

Anatomy and physiology of the afferent visual system.

The efficient organization of the human afferent visual system meets enormous computational challenges. Once visual information is received by the eye, the signal is relayed by the retina, optic nerve, chiasm, tracts, lateral geniculate nucleus, and optic radiations to the striate cortex and extrastriate association cortices for final visual processing. At each stage, the functional organization of these circuits is derived from their anatomical and structural relationships. In the retina, photoreceptors convert photons of light to an electrochemical signal that is relayed to retinal ganglion cells. Ganglion cell axons course through the optic nerve, and their partial decussation in the chiasm brings together corresponding inputs from each eye. Some inputs follow pathways to mediate pupil light reflexes and circadian rhythms. However, the majority of inputs arrive at the lateral geniculate nucleus, which relays visual information via second-order neurons that course through the optic radiations to arrive in striate cortex. Feedback mechanisms from higher cortical areas shape the neuronal responses in early visual areas, supporting coherent visual perception. Detailed knowledge of the anatomy of the afferent visual system, in combination with skilled examination, allows precise localization of neuropathological processes and guides effective diagnosis and management of neuro-ophthalmic disorders.

Finding the imposter: brain connectivity of lesions causing delusional misidentifications

See McKay and Furl (doi:10.1093/aww323) for a scientific commentary on this article. Focal brain injury can sometimes lead to bizarre symptoms, such as the delusion that a family member has been replaced by an imposter (Capgras syndrome). How a single brain lesion could cause such a complex disorder is unclear, leading many to speculate that concurrent delirium, psychiatric disease, dementia, or a second lesion is required. Here we instead propose that Capgras and other delusional misidentification syndromes arise from single lesions at unique locations within the human brain connectome. This hypothesis is motivated by evidence that symptoms emerge from sites functionally connected to a lesion location, not just the lesion location itself. First, 17 cases of lesion-induced delusional misidentifications were identified and lesion locations were mapped to a common brain atlas. Second, lesion network mapping was used to identify brain regions functionally connected to the lesion locations. Third, regions involved in familiarity perception and belief evaluation, two processes thought to be abnormal in delusional misidentifications, were identified using meta-analyses of previous functional magnetic resonance imaging studies. We found that all 17 lesion locations were functionally connected to the left retrosplenial cortex, the region most activated in functional magnetic resonance imaging studies of familiarity. Similarly, 16 of 17 lesion locations were functionally connected to the right frontal cortex, the region most activated in functional magnetic resonance imaging studies of expectation violation, a component of belief evaluation. This connectivity pattern was highly specific for delusional misidentifications compared to four other lesion-induced neurological syndromes (P < 0.0001). Finally, 15 lesions causing other types of delusions were connected to expectation violation (P < 0.0001) but not familiarity regions, demonstrating specificity for delusion content. Our results provide potential neuroanatomical correlates for impaired familiarity perception and belief evaluation in patients with delusional misidentifications. More generally, we demonstrate a mechanism by which a single lesion can cause a complex neuropsychiatric syndrome based on that lesion’s unique pattern of functional connectivity, without the need for pre-existing or hidden pathology.

Paralytic Strabismus: Third, Fourth, and Sixth Nerve Palsy

Eye movement abnormalities constitute an important clinical sign that can be a manifestation of dysfunction of cranial nerves III, IV, and VI (the 3 ocular motor nerves). Specific motility deficits often have highly localizing value within the neuroaxis, serving to refine a differential diagnosis and guide management. This article reviews the key anatomic concepts, clinical presentation, differential diagnosis, and management of ocular motor nerve palsies. Dysfunction of an ocular motor nerve must be distinguished from other causes of abnormal eye movements, such as myasthenia gravis or thyroid eye disease, which are outside the scope of this article.

Management of Potential Neurocysticercosis in Patients with HIV Infection

In patients with human immunodeficiency virus, the diagnosis of neurocysticercosis can be complex, and the current diagnostic criteria may not apply. We report 3 cases and suggest including the CD4+ T lymphocyte count as an important factor in the proper diagnosis and treatment of patients with human immunodeficiency virus and potential neurocysticercosis.