Liesly Lee

MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study

BACKGROUND Essential tremor is the most common movement disorder and is often refractory to medical treatment. Surgical therapies, using lesioning and deep brain stimulation in the thalamus, have been used to treat essential tremor that is disabling and resistant to medication. Although often effective, these treatments have risks associated with an open neurosurgical procedure. MR-guided focused ultrasound has been developed as a non-invasive means of generating precisely placed focal lesions. We examined its application to the management of essential tremor. METHODS Our study was done in Toronto, Canada, between May, 2012, and January, 2013. Four patients with chronic and medication-resistant essential tremor were treated with MR-guided focused ultrasound to ablate tremor-mediating areas of the thalamus. Patients underwent tremor evaluation and neuroimaging at baseline and 1 month and 3 months after surgery. Outcome measures included tremor severity in the treated arm, as measured by the clinical rating scale for tremor, and treatment-related adverse events. FINDINGS Patients showed immediate and sustained improvements in tremor in the dominant hand. Mean reduction in tremor score of the treated hand was 89·4% at 1 month and 81·3% at 3 months. This reduction was accompanied by functional benefits and improvements in writing and motor tasks. One patient had postoperative paraesthesias which persisted at 3 months. Another patient developed a deep vein thrombosis, potentially related to the length of the procedure. INTERPRETATION MR-guided focused ultrasound might be a safe and effective approach to generation of focal intracranial lesions for the management of disabling, medication-resistant essential tremor. If larger trials validate the safety and ascertain the efficacy and durability of this new approach, it might change the way that patients with essential tremor and potentially other disorders are treated. FUNDING Focused Ultrasound Foundation.

A Citywide Prehospital Protocol Increases Access to Stroke Thrombolysis in Toronto

Background and Purpose— Intravenous tissue plasminogen activator for ischemic stroke is approved for eligible patients who can be treated within a 3-hour window, but treatment rates remain disappointingly low, often <5%. To improve rapid access to stroke thrombolysis in Toronto, Canada, a citywide prehospital acute stroke activation protocol was implemented by the provincial government to transport acute stroke patients directly to one of 3 regional stroke centers, bypassing local hospitals. This comprised a paramedic screening tool, ambulance destination decision rule, and formal memorandum of understanding of system stakeholders. This report describes the initial impact of the activation protocol at our regional stroke center. Methods— We compared consecutive patients with stroke arriving to our stroke center during the first 4 months of this new triage protocol (February 14 to June 14, 2005) versus the same 4-month period in 2004. Results— The protocol resulted in an immediate doubling in the number of patients with acute stroke arriving to our regional stroke center within 2.5 hours of symptom onset. We observed a 4-fold increase in patients who were eligible for and treated with tissue plasminogen activator. The tissue plasminogen activator treatment rate for ischemic stroke patients increased from 9.5% to 23.4% (P=0.01), and one in 2 patients with ischemic stroke arriving within 2.5 hours received thrombolysis during this period (one in 5 of patients with ischemic stroke overall). The median onset-to-needle time for tissue plasminogen activator-treated patients was significantly reduced. Many implementation challenges were identified and addressed. Conclusions— This prehospital triage was immediately successful in improving tissue plasminogen activator access for patients with ischemic stroke, enabling our center to achieve one of the highest tissue plasminogen activator treatment rates in North America and underscoring the need for coordinated systems of acute stroke care. Sustainability of such an initiative will be dependent on interdisciplinary teamwork, ongoing paramedic training, adequate hospital staffing, bed availability, and repatriation agreements with community hospitals.

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis

BACKGROUND On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. METHODS During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2‐weighted MRI, cumulative number of new lesions enhanced on T1‐weighted MRI [“enhancing lesions”], and cumulative combined number of unique lesions [new enhancing lesions on T1‐weighted MRI plus new and newly enlarged lesions on T2‐weighted MRI]). RESULTS A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24‐month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. CONCLUSIONS The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887.)

Peroxisomal D-bifunctional protein deficiency: three adults diagnosed by whole-exome sequencing.

Objective: To determine the causative genetic lesion in 3 adult siblings with a slowly progressive, juvenile-onset phenotype comprising cerebellar atrophy and ataxia, intellectual decline, hearing loss, hypogonadism, hyperreflexia, a demyelinating sensorimotor neuropathy, and (in 2 of 3 probands) supratentorial white matter changes, in whom numerous prior investigations were nondiagnostic. Methods: The patients’ initial clinical assessment included history and physical examination, cranial MRI, and nerve conduction studies. We performed whole-exome sequencing of all 3 probands, followed by variant annotation and selection of rare, shared, recessive coding changes to identify the gene responsible. We next performed a panel of peroxisomal investigations in blood and cultured fibroblasts, including assessment of D-bifunctional protein (DBP) stability and activity by immunoblot and enzymologic methods, respectively. Results: Exome sequencing identified compound heterozygous mutations in HSD17B4, encoding peroxisomal DBP, in all 3 probands. Both identified mutations alter a conserved residue within the active site of DBP’s enoyl-CoA hydratase domain. Routine peroxisomal screening tests, including very long-chain fatty acids and phytanic acid, were normal. DBP enzymatic activity was markedly reduced. Conclusion: Exome sequencing provides a powerful and elegant tool in the specific diagnosis of “mild” or “atypical” neurometabolic disorders. Given the broad differential diagnosis and the absence of detectable biochemical abnormalities in blood, molecular testing of HSD17B4 should be considered as a first-line investigation in patients with compatible features.

Somatosensory neurons in human thalamuc respond to speech-induced orofacial movements

As part of stereotactic surgery, microelectrode recordings of somatosensory neurons in thalamus were obtained in 5 patients. Neurons with receptive fields on the lips and tongue were consistently activated when these structures were involved in production of speech sounds. The magnitudes of these responses were similar to those elicited by experimentally applied mechanical stimuli, suggesting that speech-induced somatosensory inputs are not suppressed at the thalamic level.

Robust Perfusion Deficits in Cognitively Impaired Patients with Secondary-Progressive Multiple Sclerosis

These authors investigated the effect of perfusion deficits on patients with MS with cognitive impairment. In 45 patients with secondary-progressive MS, cognition was assessed using standardized clinical tests and CBF and CBV perfusion maps were obtained, analyzed, and correlated with gray and white matter and lesion volumes. Perfusion in the deep gray matter nuclei and frontal cortex was significantly reduced in cognitively impaired patients with MS despite no significant differences regarding gray matter, white matter, and lesion volumes. Of the cognitive parameters investigated, information processing speed was most affected. BACKGROUND AND PURPOSE: Cognitive impairment is a common, disabling symptom of MS. We investigated the impact of cerebral perfusion and brain and lesion volumetry on cognitive performance in 45 patients with SPMS by using MR imaging. MATERIALS AND METHODS: Cognition was assessed by using a standard battery, the Minimal Assessment of Cognitive Function in Multiple Sclerosis. qCBF and qCBV maps were analyzed by using SPM and PLS. SPM was also used to conduct the GM, WM, and WML volumetric analyses. RESULTS: Both SPM and PLS demonstrated significantly reduced qCBV in the superior medial frontal cortex of impaired patients. PLS also revealed significantly lower qCBV in the bilateral thalami and caudate nuclei of impaired patients and identified a pattern of significantly attenuated qCBF similar to that of qCBV. Performance on the Symbol Digit Modalities Test, which assesses information-processing speed, correlated most strongly overall with cerebral perfusion. Focal (ie, voxelwise) analyses of GM, WM, and WML volume revealed no significant differences between patients with and without cognitive impairment, though global GM volume was significantly decreased and global WML volume was significantly increased in impaired patients. CONCLUSIONS: These results suggest that cognitively impaired patients with SPMS exhibit robust perfusion deficits in cortical and subcortical GM and impaired processing speed.

Decreased Frontal Lobe Gray Matter Perfusion in Cognitively Impaired Patients with Secondary-Progressive Multiple Sclerosis Detected by the Bookend Technique

BACKGROUND AND PURPOSE: There is increasing evidence implicating microvascular impairment in MS pathogenesis. Perfusion imaging offers a unique opportunity to investigate the functional impact of GM pathology. We sought to quantify differences in MR imaging–based bookend-derived cerebral perfusion between cognitively impaired and nonimpaired patients with SPMS. MATERIALS AND METHODS: Patients were prospectively recruited and assessed using MR imaging and the standard cognitive battery called the Minimal Assessment of Cognitive Function in MS. Patients exhibiting impairment on ≥2 individual tests were classified as cognitively impaired. Healthy controls were prospectively recruited and assessed using MR imaging to validate bookend assumptions. Structural and perfusion scans were coregistered and partitioned into anatomic brain regions and tissue compartments. Clinical and radiologic characteristics were compared between patients with and without impairment to identify potential confounders. A Bonferroni adjusted P value threshold (P < .005) was used for lobar and sublobar level analyses to correct for multiple comparisons. RESULTS: Thirty-seven patients with SPMS (age 56 ± 9 years; 23 women, 14 men) and 10 age- and sex-matched healthy controls were recruited. Bookend assumptions were found to be valid in MS. GM and WM qCBV were all globally reduced in impaired patients. After adjusting for potential confounders while examining sublobar level perfusion, only GM qCBV was significantly different between cognitive groups, and this hypoperfusion localized to the bilateral medial superior frontal regions and left inferior, middle, and superior frontal regions (P < .005) of impaired patients compared with nonimpaired patients. GM qCBV accounted for 22.5% of the model variance compared with a model including only confounders (P = .0007). CONCLUSIONS: Bookend-derived GM qCBV was significantly reduced in cognitively impaired patients with SPMS in functionally relevant brain regions.

Impact of a formal mentoring program on academic promotion of Department of Medicine faculty: A comparative study

Abstract Purpose: To evaluate the impact of a formal mentoring program on time to academic promotion and differences in gender-based outcomes. Methods: Comparisons of time to promotion (i) before and after implementation of a formal mentoring program and (ii) between mentored and non-mentored faculty matched for covariates. Using paired-samples t-testing and mixed repeated measures ANCOVA, we explored the effect of mentor assignment and influence of gender on time to promotion. Results: Promotional data from 1988 to 2010 for 382 faculty members appointed before 2003 were compared with 229 faculty members appointed in 2003 or later. Faculty appointed in 2003 or later were promoted 1.2 years (mean) sooner versus those appointed before 2003 (3.7 [SD = 1.7] vs. 2.5 [SD = 2], p < 0.0001). Regardless of year of appointment, mentor assignment appears to be significantly associated with a reduction in time to promotion versus non-mentored (3.4 [SD = 2.4] vs. 4.4 [SD = 2.6], p = 0.011). Gender effects were statistically insignificant. Post hoc analyses of time to promotion suggested that observed differences are not attributable to temporal effects, but rather assignment to a mentor. Conclusions: Mentoring was a powerful predictor of promotion, regardless of the year of appointment and likely benefited both genders equally. University resource allocation in support of mentoring appears to accelerate faculty advancement.

Multiple sclerosis fatigue is associated with reduced psychomotor vigilance.

BACKGROUND Fatigue is common and disabling in multiple sclerosis, yet its physiologic substrates remain poorly defined. The aim of this study was to determine the relationship between fatigue and an objective measure of alertness in MS patients. METHODS This study enrolled 49 consecutive MS clinic patients at two academic hospitals in Toronto. Alertness was assessed with the psychomotor vigilance test (PVT), a ten-minute reaction-time test that measures attention and is sensitive to sleep loss. Patients with visual impairment or arm weakness were excluded. Validated tools were used to assess fatigue, disability, mood, and pain. RESULTS The average age was 43; 65% were women. Median EDSS was 2.0 (range 0-7.5). Fifty-five percent reported a high impact of fatigue on their lives. Psychomotor vigilance test performance was worse than in an age- and sex-matched population, with a mean reaction time of 315 msecs and 3.98 lapses >500 msec (p<0.001). In a multiple regression analysis, fatigue was the most significantly correlated factor with mean PVT reaction time (p<0.05), and disability was also significantly correlated (p<0.01). Mood and pain did not correlate with the PVT. Eighteen (37%) reported often experiencing restlessness in their legs at night. CONCLUSION Subjective fatigue and disability were associated with poor performance on alertness testing in MS patients. This research highlights a potential role for psychomotor vigilance testing in providing a standardized assessment tool for an important aspect of MS-related fatigue.

Perfusion reduction in the absence of structural differences in cognitively impaired versus unimpaired RRMS patients.

Background: Cognitive impairment affects 40%–68% of relapsing-remitting multiple sclerosis (RRMS) patients. Gray matter (GM) demyelination is complicit in cognitive impairment, yet cortical lesions are challenging to image clinically. We wanted to determine whether cortical cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) differences exist between cognitively impaired (CI) and unimpaired (NI) RRMS. Methods: Prospective study of healthy controls (n = 19), CI (n = 20), and NI (n = 19) undergoing magnetic resonance imaging (MRI) and cognitive testing <1 week apart. White matter (WM) T2 hyperintense lesions and T1 black holes were traced. General linear regression assessed the relationship between lobar WM volume and cortical and WM CBF, CBV, and MTT. Relationship between global and lobar cortical CBF, CBV, and MTT and cognitive impairment was tested using a generalized linear model. Adjusted Bonferroni p < 0.005 was considered significant. Results: No significant differences for age, gender, disease duration, and any fractional brain or lesion volume were demonstrated for RRMS subgroups. Expanded Disability Status Scale (EDSS) and Hospital Anxiety and Depression Scale–Depression (HADS-D) were higher in CI. Lobar cortical CBF and CBV were associated with cognitive impairment (p < 0.0001) after controlling for confounders. Cortical CBV accounted for 7.2% of cognitive impairment increasing to 8.7% with cortical CBF (p = 0.06), while WM and cortical CBF accounted for 8.2% of variance (p = 0.04). Conclusion: Significant cortical CBF and CBV reduction was present in CI compared to NI in the absence of structural differences.