Daniel A. Drubach

Imaging correlates of posterior cortical atrophy

The aim of this study was to compare patterns of cerebral atrophy on MRI, and neurochemistry on magnetic resonance spectroscopy (MRS), in patients with posterior cortical atrophy (PCA) and typical Alzheimers disease (AD). Voxel-based morphometry was used to assess grey matter atrophy in 38 patients with PCA, 38 patients with typical AD, and 38 controls. Clinical data was assessed in all PCA patients. Single voxel (1)H MRS located in the posterior cingulate was analyzed in a subset of patients with PCA, typical AD, and control subjects. PCA showed a pattern of atrophy affecting occipital, parietal and posterior temporal lobes, compared to controls. The pattern was bilateral, but more severe on the right. Patients with PCA showed greater atrophy in the right visual association cortex than patients with typical AD, whereas those with AD showed greater atrophy in the left hippocampus than those with PCA. (1)H MRS suggested loss of neuronal integrity and glial activation in subjects with PCA and typical AD. The differing patterns of atrophy on MRI suggest that PCA should be considered a distinct entity from typical AD.

Imaging correlates of pathology in corticobasal syndrome

Background: Corticobasal syndrome (CBS) can be associated with different underlying pathologies that are difficult to predict based on clinical presentation. The aim of this study was to determine whether patterns of atrophy on imaging could be useful to help predict underlying pathology in CBS. Methods: This was a case-control study of 24 patients with CBS who had undergone MRI during life and came to autopsy. Pathologic diagnoses included frontotemporal lobar degeneration (FTLD) with TDP-43 immunoreactivity in 5 (CBS-TDP), Alzheimer disease (AD) in 6 (CBS-AD), corticobasal degeneration in 7 (CBS-CBD), and progressive supranuclear palsy in 6 (CBS-PSP). Voxel-based morphometry and atlas-based parcellation were used to assess atrophy across the CBS groups and compared to 24 age- and gender-matched controls. Results: All CBS pathologic groups showed gray matter loss in premotor cortices, supplemental motor area, and insula on imaging. However, CBS-TDP and CBS-AD showed more widespread patterns of loss, with frontotemporal loss observed in CBS-TDP and temporoparietal loss observed in CBS-AD. CBS-TDP showed significantly greater loss in prefrontal cortex than the other groups, whereas CBS-AD showed significantly greater loss in parietal lobe than the other groups. The focus of loss was similar in CBS-CBD and CBS-PSP, although more severe in CBS-CBD. Conclusions: Imaging patterns of atrophy in CBS vary according to pathologic diagnosis. Widespread atrophy points toward a pathologic diagnosis of FTLD-TDP or AD, with frontotemporal loss suggesting FTLD-TDP and temporoparietal loss suggesting AD. On the contrary, more focal atrophy predominantly involving the premotor and supplemental motor area suggests CBD or PSP pathology.

Autoimmune Dementia: Clinical Course and Predictors of Immunotherapy Response

OBJECTIVE To define the diagnostic characteristics and predictors of treatment response in patients with suspected autoimmune dementia. PATIENTS AND METHODS Between January 1, 2002, and January 1, 2009, 72 consecutive patients received immunotherapy for suspected autoimmune dementia. Their baseline clinical, radiologic, and serologic characteristics were reviewed and compared between patients who were responsive to immunotherapy and those who were not. Patients were classified as responders if the treating physician had reported improvement after immunotherapy (documented in 80% by the Kokmen Short Test of Mental Status, neuropsychological testing, or both). RESULTS Initial immunotherapeutic regimens included methylprednisolone in 56 patients (78%), prednisone in 12 patients (17%), dexamethasone in 2 patients (3%), intravenous immune globulin in 1 patient (1%), and plasma exchange in 1 patient (1%). Forty-six patients (64%) improved, most in the first week of treatment. Thirty-five percent of these immunotherapy responders were initially diagnosed as having a neurodegenerative or prion disorder. Pretreatment and posttreatment neuropsychological score comparisons revealed improvement in almost all cognitive domains, most notably learning and memory. Radiologic or electroencephalographic improvements were reported in 22 (56%) of 39 patients. Immunotherapy responsiveness was predicted by a subacute onset (P<.001), fluctuating course (P<.001), tremor (P=.007), shorter delay to treatment (P=.005), seropositivity for a cation channel complex autoantibody (P=.01; neuronal voltage-gated potassium channel more than calcium channel or neuronal acetylcholine receptor), and elevated cerebrospinal fluid protein (>100 mg/dL) or pleocytosis (P=.02). Of 26 immunotherapy-responsive patients followed up for more than 1 year, 20 (77%) relapsed after discontinuing immunotherapy. CONCLUSION Identification of clinical and serologic clues to an autoimmune dementia allows early initiation of immunotherapy, and maintenance if needed, thus favoring an optimal outcome.

Positron Emission Tomography–Computed Tomography in Paraneoplastic Neurologic Disorders: Systematic Analysis and Review

OBJECTIVE To evaluate the cancer detection rate of whole-body positron emission tomography-computed tomography (PET-CT) in a paraneoplastic neurologic context. DESIGN Retrospective medical record review. SETTING Mayo Clinic, Rochester, Minnesota. PATIENTS Fifty-six consecutive patients with clinically suspected paraneoplastic neurologic disorders who underwent PET-CT after negative standard evaluations, including CT. MAIN OUTCOME MEASURE Rate of cancer detection. RESULTS Abnormalities suggestive of cancer were detected using PET-CT in 22 patients (39%); 10 patients (18%) had cancer confirmed histologically. Cancers detected (limited stage in 9 of 10 patients and extratruncal in 4) were as follows: 2 thyroid papillary cell carcinomas, 3 solitary lymph nodes with unknown primary (2 adenocarcinomas and 1 small cell carcinoma), 1 tonsil squamous cell carcinoma, 3 lung carcinomas (1 adenocarcinoma, 1 small cell, and 1 squamous cell), and 1 colon adenocarcinoma. Detection of a well-characterized neuronal nuclear or cytoplasmic paraneoplastic autoantibody was associated with a successful PET-CT-directed cancer search (P < .001). Detection of limited-stage cancer facilitated early initiation of oncologic treatments and immunotherapy; cancer remission was reported in 7 patients, and sustained improvements in neurologic symptoms were reported in 5 (median follow-up, 11 months; range, 2-48 months). Combined data from 2 previous studies using conventional PET alone (123 patients) revealed that 28% of patients had a PET abnormality suggestive of cancer and that 12% had a cancer diagnosis. CONCLUSION In a paraneoplastic neurologic context, PET-CT improves the detection of cancers when other screening test results are negative, particularly in the setting of seropositivity for a neuronal nuclear or cytoplasmic autoantibody marker of cancer.

Prevalence of Sleep Disturbance in Closed Head Injury Patients in a Rehabilitation Unit

Traumatic brain injury (TBI) is a leading cause of disability in young people in the United States. Disorders of arousal and attention are common in closed head injury (CHI). Daytime drowsiness impairs participation in rehabilitation, whereas nighttime wakefulness leads to falls and behavioral disturbances. Sleep disturbances in TBI reported in the literature have included excessive daytime somnolence, sleep phase cycle disturbance, narcolepsy, and sleep apnea. Although well known to the clinician treating these patients, the extent and prevalence of disrupted sleep in patients in an acute inpatient rehabilitation unit has not been described. Objective. To determine the prevalence of sleep wake cycle disturbance (SWCD) in patients with CHI in a TBI rehabilitation unit. Design. Prospective observational. Setting. Inpatient specialized brain injury rehabilitation unit. Patients. Thirty-one consecutive admissions to a brain injury rehabilitation unit with the diagnosis of CHI. Results. Twenty-one patients (68%) had aberrations of nighttime sleep. There was no significant difference in Glasgow Coma Score on admission to trauma nor was there any significant difference in age between the affected and unaffected groups. Patients with SWCD had longer stays in both the trauma center (P < .003) and the rehabilitation center (P < .03). Conclusions. There is a high prevalence of SWCD in CHI patients admitted to a brain injury rehabilitation unit. Patients with SWCD have longer stays in both acute and rehabilitation settings and may be a marker for more severe injury.

Frontotemporal brain sagging syndrome An SIH-like presentation mimicking FTD

Background: Behavioral variant frontotemporal dementia (bvFTD) is a relatively well-defined clinical syndrome. It is associated with frontal and temporal lobe structural/metabolic changes and pathologic findings of a neurodegenerative disease. We have been evaluating patients with clinical and imaging features partially consistent with bvFTD but with evidence also suggestive of brain sagging, which we refer to as frontotemporal brain sagging syndrome (FBSS). Methods: Retrospective medical chart review to identify all patients seen at our institution between 1996 and 2010, who had a clinical diagnosis of FTD and imaging evidence of brain sag. Results: Eight patients, 7 male and 1 female, were diagnosed with FBSS. The median age at symptom onset was 53 years. All patients had insidious onset and slow progression of behavioral and cognitive dysfunction accompanied by daytime somnolence and headache. Of the 5 patients with functional imaging, all showed evidence of hypometabolism of the frontotemporal regions. On brain MRI, all patients had evidence of brain sagging with distortion of the brainstem; 3 patients had diffuse pachymeningeal enhancement. CSF opening pressure was varied and CSF protein was mildly elevated. A definite site of CSF leak was not identified by myelogram or cisternography, except in one patient with a site highly suggestive of leak who subsequently underwent surgery confirming a CSF leak. In 2 patients with a neuropathologic examination, there was no evidence of a neurodegenerative disease. Conclusions: This case series demonstrates that FBSS may mimic typical bvFTD but should be recognized as an unusual presentation that is potentially treatable.

Psychiatric Manifestations of Voltage-Gated Potassium-Channel Complex Autoimmunity

The authors describe the neuropsychiatric spectrum of voltage-gated potassium-channel complex (VGKC) autoimmunity among 67 seropositive patients; 2 had initially been assigned a primary psychiatric diagnosis. Diverse manifestations were recorded, often affective-predominant. Symptoms for 24 patients with florid presentations included confusion, 92%; memory impairment, 75%; personality change, 58%; depression, 33%; and anxiety, 29%. Of 15 who received immunotherapy, 67% improved. Forty-three patients with milder presentations or low positive VGKC complex Ab values are also described. Neuropsychiatric presentations were significantly associated with higher autoantibody values. Improvements were most evident in patients treated early, which emphasizes the need for early diagnosis and immunotherapy initiation.

18F-FDG PET in Posterior Cortical Atrophy and Dementia with Lewy Bodies

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) have both been associated with occipital lobe hypometabolism on 18F-FDG PET, whereas relative sparing of posterior cingulate metabolism compared with precuneus/cuneus (i.e., cingulate island sign) is a feature of DLB. We aimed to determine whether patterns of hypometabolism or the cingulate island sign differed between PCA and DLB. Methods: Sixteen clinically diagnosed PCA and 13 probable DLB subjects underwent 18F-FDG PET. All PCA subjects showed β-amyloid deposition on PET scanning. Regional hypometabolism was assessed compared with a control cohort (n = 29) using voxel- and region-level analyses in statistical parametric mapping. A ratio of metabolism in the posterior cingulate to precuneus plus cuneus was calculated to assess the cingulate island sign. In addition, the 18F-FDG PET scans were visually assessed to determine whether the cingulate island sign was present in each subject. Results: PCA and DLB showed overlapping patterns of hypometabolism involving the lateral occipital lobe, lingual gyrus, cuneus, precuneus, posterior cingulate, inferior parietal lobe, supramarginal gyrus, striatum, and thalamus. However, DLB showed greater hypometabolism in the medial occipital lobe, orbitofrontal cortex, anterior temporal lobe, and caudate nucleus than PCA, and PCA showed more asymmetric patterns of hypometabolism than DLB. The cingulate island sign was present in both DLB and PCA, although it was more asymmetric in PCA. Conclusion: Regional hypometabolism overlaps to a large degree between PCA and DLB, although the degree of involvement of the frontal and anterior temporal lobes and the presence of asymmetry could be useful in differential diagnosis.

Manipulation of Central Nervous System Plasticity: A New Dimension in the Care of Neurologically Impaired Patients

Research in the neurosciences in recent decades has shown that the central nervous system is not a structurally static organ as was believed previously, but instead is a dynamic system that constantly undergoes structural and functional reorganization. The term brain plasticity refers to the constant cellular and intercellular modifications that occur during normal development and after neurologic injury and result in changes in neurologic function. The discovery that central nervous system plasticity after injury can be directed toward functional improvement with use of specific modalities has opened up a new dimension in the care of the neurologically impaired patient, termed restorative neurology.

Steroid-responsive encephalopathy subsequently associated with Alzheimer's disease pathology: A case series

Background: Steroid-responsive encephalopathies can be considered vasculitic or non-vasculitic. Clinicopathological studies of non-vasculitic steroid-responsive encephalopathy are unusual, but can explain the range of diagnoses consistent with a steroid-responsive presentation in life. Objective: To extend the range of clinical features and pathological findings consistent with steroid-responsive encephalopathy. Design, methods, and patients: A clinicopathological case series of four patients (two women, ages 54–71 years) with steroid-responsive encephalopathy followed at this institution until the time of death. Results: Clinical features were suggestive of Creutzfeld–Jakob disease (CJD), dementia with Lewy bodies (DLB), and parkinsonism, but pathological examination revealed only Alzheimers disease-related findings without evidence of Lewy bodies or prion disease in all cases. All patients demonstrated marked, sustained improvement following steroid treatment, based on clinical, magnetic resonance imaging, and/or electroencephalogram studies. Alzheimers disease was not diagnosed in life due to the atypical clinical features, lack of hippocampal atrophy on brain imaging, and a dramatic symptomatic response to steroids. Conclusions: Steroid-responsive encephalopathy is the clinical presentation of some patients with Alzheimers disease-related pathology at autopsy, and can be consistent with the clinical diagnoses of parkinsonism, DLB, or CJD disease in life.