ANCA-associated vasculitis presenting with isolated neurological manifestations in a patient with cocaine abuse: a case report and literature review.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare conditions predominantly affecting small vessels of skin, musculoskeletal, pulmonary, renal, and rarely central and peripheral nervous systems. Isolated neurological manifestations of AAV are uncommon and challenging to diagnose. Cocaine has been reported as a potential trigger for the development of AAV. There are only a few case reports of isolated neurological involvement in cocaine-induced AAV with poorly characterized histopathological features. We present a unique case of AAV with isolated neurological manifestations presenting with multiple cranial neuropathies, leptomeningeal enhancement on imaging and histopathologic evidence of small-vessel vasculitis in the leptomeninges and brain and extensive dural fibrosis in a patient with cocaine abuse. The patient's progressive neurological deficits were controlled after starting immunosuppression with rituximab and prednisone. We also reviewed the literature to provide the diagnostic overview of AAV and evaluate intervention options. To our knowledge, this is the first case of AAV with isolated neurological manifestations and histopathologic evidence of small-vessel vasculitis in a patient with cocaine abuse. Patients with multiple cranial neuropathies and meningeal involvement should be screened for AAV, especially if they have a history of cocaine abuse.

Bilateral Acute Hippocampal Ischemia in Two Patients Abusing Cocaine: What is the Outcome?

Hippocampal ischemia is a rare complication of cocaine abuse that has been thought to arise from vasospasm, anoxic injury, and/or catecholaminergic excitotoxicity. We present two cases of patients abusing cocaine, who presented with an acute onset anterograde amnesia due to bilateral hippocampal ischemia, and had different outcomes. Case 1 is a 49-year-old male with a history of IV heroin abuse who presented after being found down for an unknown period of time. He awoke with no memory of events leading up to hospitalization and was unable to retain new information. Urine toxicology was positive for cocaine and opiates. Traditional vascular risk factors included obesity, hypertension, and hyperlipidemia. His recovery was complicated by continued drug use and one episode of cardiac arrest. Despite cognitive rehabilitation, only minimal improvements in his anterograde memory were observed during his annual follow-up. Case 2 is a 23-year-old male with a history of attention deficit disorder treated with dexmethylphenidate and a history of consistent marijuana and cocaine abuse, who presented with nausea, vomiting, chest pain, shortness of breath, and acute-onset short-term memory loss. Urine toxicology was negative for cocaine and opiates and positive for marijuana. He had no known vascular risk factors. With cognitive rehabilitation and discontinuation of illicit drug use, he demonstrated a significant improvement in his memory function over the course of six months. Brain MRI in both patients showed symmetric bilateral hippocampal diffusion restriction without post-contrast enhancement with corresponding hyperintensities on fluid-attenuated inversion recovery sequences. In both patients, cerebrospinal fluid (CSF) studies were unremarkable for inflammation or infection, and electroencephalograms were normal in awake and drowsy states. Bilateral hippocampal ischemia should be considered as a potential cause of acute onset anterograde amnesia in patients with a history of cocaine abuse. Other substances such as heroin and dexmethylphenidate may potentially increase susceptibility for hippocampal ischemia in patients using cocaine. Discontinuation of illicit drug abuse can influence the degree of recovery from acute bilateral hippocampal ischemia.

Brain and cord imaging features in neuromyelitis optica spectrum disorders.

OBJECTIVES: To validate imaging features able to discriminate neuromyelitis optica spectrum disorders from multiple sclerosis with conventional magnetic resonance imaging (MRI). METHODS: In this cross-sectional study, brain and spinal cord scans were evaluated from 116 neuromyelitis optica spectrum disorder patients (98 seropositive and 18 seronegative) in chronic disease phase and 65 age-, sex-, and disease duration-matched multiple sclerosis patients. To identify independent predictors of neuromyelitis optica diagnosis, after assessing the prevalence of typical/atypical findings, the original cohort was 2:1 randomized in a training sample (where a multivariate logistic regression analysis was run) and a validation sample (where the performance of the selected variables was tested and validated). RESULTS: Typical brain lesions occurred in 50.9% of neuromyelitis optica patients (18.1% brainstem periventricular/periaqueductal, 32.7% periependymal along lateral ventricles, 3.4% large hemispheric, 6.0% diencephalic, 4.3% corticospinal tract), 72.2% had spinal cord lesions (46.3% long transverse myelitis, 36.1% short transverse myelitis), 37.1% satisfied 2010 McDonald criteria, and none had cortical lesions. Fulfillment of at least 2 of 5 of absence of juxtacortical/cortical lesions, absence of periventricular lesions, absence of Dawson fingers, presence of long transverse myelitis, and presence of periependymal lesions along lateral ventricles discriminated neuromyelitis optica patients in both training (sensitivity = 0.92, 95% confidence interval [CI] = 0.84-0.97; specificity = 0.91, 95% CI = 0.78-0.97) and validation samples (sensitivity = 0.82, 95% CI = 0.66-0.92; specificity = 0.91, 95% CI = 0.71-0.99). MRI findings and criteria performance were similar irrespective of serostatus. INTERPRETATION: Although up to 50% of neuromyelitis optica patients have no typical lesions and a relatively high percentage of them satisfy multiple sclerosis criteria, several easily applicable imaging features can help to distinguish neuromyelitis optica from multiple sclerosis. ANN NEUROL 2019;85:371-384.

Dynamic volumetric changes of hippocampal subfields in clinically isolated syndrome patients: A 2-year MRI study.

BACKGROUND: Different subregional patterns of hippocampal involvement have been observed in diverse multiple sclerosis (MS) phenotypes. OBJECTIVE: To evaluate the occurrence of regional hippocampal variations in clinically isolated syndrome (CIS) patients, their relationships with focal white matter (WM) lesions, and their prognostic implications. METHODS: Brain dual-echo and three-dimensional (3D) T1-weighted scans were acquired from 14 healthy controls and 36 CIS patients within 2 months from clinical onset and after 3, 12, and 24 months. Radial distance distribution was assessed using 3D parametric surface mesh models. A cognitive screening was also performed. RESULTS: Patients showed clusters of reduced radial distance in the Cornu Ammonis 1 from month 3, progressively extending to the subiculum, negatively correlated with ipsilateral T2 and T1 lesion volume. Increased radial distance appeared in the right dentate gyrus after 3 (p < 0.05), 12, and 24 (p < 0.001) months, and in the left one after 3 and 24 months (p < 0.001), positively correlated with lesional measures. Hippocampal volume variations were more pronounced in patients converting to MS after 24 months and did not correlate with cognitive performance. CONCLUSION: Regional hippocampal changes occur in CIS, are more pronounced in patients converting to MS, and are modulated by focal WM lesions.

Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study.

BACKGROUND: In 2016, the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network proposed modifications to the MRI criteria to define dissemination in space (DIS) and time (DIT) for the diagnosis of multiple sclerosis in patients with clinically isolated syndrome (CIS). Changes to the DIS definition included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested. We compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for multiple sclerosis diagnosis in a large multicentre cohort of patients with CIS to provide evidence to guide revisions of multiple sclerosis diagnostic criteria. METHODS: Brain and spinal cord MRI and optic nerve assessments from patients with typical CIS suggestive of multiple sclerosis done less than 3 months from clinical onset in eight European multiple sclerosis centres were included in this retrospective study. Eligible patients were 16-60 years, and had a first CIS suggestive of CNS demyelination and typical of relapsing-remitting multiple sclerosis, a complete neurological examination, a baseline brain and spinal cord MRI scan obtained less than 3 months from clinical onset, and a follow-up brain scan obtained less than 12 months from CIS onset. We recorded occurrence of a second clinical attack (clinically definite multiple sclerosis) at months 36 and 60. We evaluated MRI criteria performance for DIS, DIT, and DIS plus DIT with a time-dependent receiver operating characteristic curve analysis. FINDINGS: Between June 16, 1995, and Jan 27, 2017, 571 patients with CIS were screened, of whom 368 met all study inclusion criteria. At the last evaluation (median 50·0 months [IQR 27·0-78·4]), 189 (51%) of 368 patients developed clinically definite multiple sclerosis. At 36 months, the two DIS criteria showed high sensitivity (2010 McDonald 0·91 [95% CI 0·85-0·94] and 2016 MAGNIMS 0·93 [0·88-0·96]), similar specificity (0·33 [0·25-0·42] and 0·32 [0·24-0·41]), and similar area under the curve values (AUC; 0·62 [0·57-0·67] and 0·63 [0·58-0·67]). Performance was not affected by inclusion of symptomatic lesions (sensitivity 0·92 [0·87-0·96], specificity 0·31 [0·23-0·40], AUC 0·62 [0·57-0·66]) or cortical lesions (sensitivity 0·92 [0·87-0·95], specificity 0·32 [0·24-0·41], AUC 0·62 [0·57-0·67]). Requirement of three periventricular lesions resulted in slightly lower sensitivity (0·85 [0·78-0·90], slightly higher specificity (0·40 [0·32-0·50], and similar AUC (0·63 [0·57-0·68]). Inclusion of optic nerve evaluation resulted in similar sensitivity (0·92 [0·87-0·96]), and slightly lower specificity (0·26 [0·18-0·34]) and AUC (0·59 [0·55-0·64]). AUC values were also similar for DIT (2010 McDonald 0·61 [0·55-0·67] and 2016 MAGNIMS 0·61 [0·55-0·66]) and DIS plus DIT (0·62 [0·56-0·67] and 0·64 [0·58-0·69]). INTERPRETATION: The 2016 MAGNIMS criteria showed similar accuracy to the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis. Inclusion of symptomatic lesions is expected to simplify the clinical use of MRI criteria without reducing accuracy, and our findings suggest that needing three lesions to define periventricular involvement might slightly increase specificity, suggesting that these two factors could be considered during further revisions of multiple sclerosis diagnostic criteria. FUNDING: UK MS Society, National Institute for Health Research University College London Hospitals Biomedical Research Centre, Dutch MS Research Foundation.

Bladder dysfunction in multiple sclerosis: a 6-year follow-up study.

Bladder dysfunction (BD) is the most common autonomic disturbance in multiple sclerosis, but often overlooked and undertreated. The purpose of this longitudinal study was to explore the changes in the frequency of BD symptoms in MS cohort after a period of 3 and 6 years of follow-up, as well as to investigate the correlations between the presence of BD symptoms and both clinical characteristics and the health-related quality of life (HRQoL) at each subsequent point of estimation. The study population comprises a cohort of 93 patients with MS (McDonald's criteria, 2001). At each time point (baseline, and at the 3- and 6-year follow-up) of estimation, Expanded Disability Status Scale, Hamilton Rating Scale for Depression, Fatigue Severity Scale, Szasz Sexual Functioning Scale and HRQoL (measured by MSQoL-54) were assessed. The proportion of patients with at least one symptom of BD significantly increased over time, for both men and women (from 48.1% at baseline to 51.9% after 3 years and to 71.4% after 6 years of follow-up for males and from 45.5% at baseline to 50.0% after 3 years and to 66.7% after 6 years of follow-up for females). The most common BD problem was urgency of urination. The presence of BD was statistically significantly associated with higher level of physical disability, sexual dysfunction and HRQoL at each point of follow-up, for both men and women. Our results suggested outstanding frequency of BD in patients with MS, with increasing tendency over time.

IL-11 Induces Th17 Cell Responses in Patients with Early Relapsing-Remitting Multiple Sclerosis.

Clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) is the earliest clinically evident phase of the disease, which may provide valuable insight into the molecular mechanisms of the initiation of the autoimmune response in MS. Our results introduce IL-11 as a new cytokine that plays a role in the autoimmune response in the early phase of the disease. IL-11 is the highest upregulated cytokine in the sera and cerebrospinal fluid from CIS patients, which is also increased in patients with clinically definitive relapsing-remitting MS in comparison with healthy control subjects. Serum IL-11 levels are significantly increased during clinical exacerbations in comparison with remissions in the same patients. CD4(+) cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11(+)CD4(+) cells is significantly increased in CIS patients in comparison with healthy control subjects. Furthermore, we have identified IL-11 as a new Th17-promoting cytokine, because it induces a differentiation of naive CD4(+) T cells into Th17 cells, as well as expansion of Th17 memory cells. Because the Th17 cytokines IL-17F, IL-21 and TNF-α, and TGF-ß induce differentiation of naive cells in the IL-11-secreting CD4(+) cells, we propose that cross-talk between IL-11(+)CD4(+) and Th17 cells may play a role in the inflammatory response in relapsing-remitting MS.

Interferon-beta and disability progression in relapsing-remitting multiple sclerosis.

OBJECTIVE: To assess the impact of interferon (IFN)-beta treatment on the progression of unremitting disability in IFN-beta treated and untreated relapsing-remitting (RR) patients with multiple sclerosis (MS) using prospective cohort study. METHODS: A cohort of 419 RRMS (236 IFN-beta-treated and 183 untreated) patients was followed for up to 7 years. Cox proportional hazards regression models adjusted for the number of relapses in the last year before first visit was used to assess the differences between the two groups for the three end points: secondary progression (SP), and sustained Expanded Disability Status Scale (EDSS) score 4 and 6. Time from disease onset was used as survival time variable. RESULTS: The IFN-beta-treated group showed a highly significant reduction (hazard ratio [HR], 0.34, 95% confidence interval [CI] 0.19-0.61, p<0.001) in the risk of SP when compared with untreated patients. There were significant differences in favor of the IFN-beta-treated group for the end point EDSS score of 4 (HR=0.45, 95%CI 0.28-0.73, p=0.001) and EDSS score of 6 (HR=0.34, 95%CI 0.16-0.75, p=0.007). CONCLUSION: This observational study further supports the notion that IFN-beta could have potential beneficial effect on disease progression in RRMS.

Wallerian and trans-synaptic degeneration contribute to optic radiation damage in multiple sclerosis: a diffusion tensor MRI study.

BACKGROUND: Optic radiation (OR) damage occurs in multiple sclerosis (MS). OBJECTIVES: The purpose of this study was to explore the contribution of local and distant mechanisms associated with OR damage in MS. METHODS: Diffusion tensor (DT) magnetic resonance imaging (MRI) tractography probability maps of the ORs were derived from 102 MS patients and 11 controls. Between-group differences of OR normal-appearing white matter (NAWM) damage and topographical distribution of OR damage were assessed using quantitative and voxel-wise analyses, considering the influence of previous optic neuritis (ON+) and T2 OR lesions (T2 OR+). RESULTS: OR NAWM diffusivity abnormalities were more severe in ON+ patients vs patients without previous optic neuritis (ON-) and T2 OR+ vs T2 OR- patients. Damage to the anterior portions of the ORs was more severe in ON+ vs ON- patients. Compared to controls and T2 OR- patients, T2 OR+ patients experienced a more distributed pattern of DT MRI abnormalities along the ORs, with an increased axial diffusivity limited to the anterior portions of the ORs. In T2 OR+ group, ON+ vs ON- patients showed DT MRI abnormalities in the middle portion of the ORs, in correspondence with focal lesions. OR damage correlated with OR T2 lesion volume, visual dysfunction and optic nerve atrophy. CONCLUSIONS: Both trans-synaptic degeneration secondary to optic nerve damage and Wallerian degeneration due to local T2 lesions contribute to OR damage in MS.

Predictive value of health-related quality of life in progression of disability and depression in persons with multiple sclerosis: a 3-year study.

In our study, we examined whether health-related quality of life (HRQoL) could predict changes in disability, depression, and fatigue in patients with multiple sclerosis (MS) over a 3-year follow-up period. A group of 109 consecutive MS patients (McDonald's criteria) referring to the Institute of Neurology, Belgrade were enrolled in the study. At two time points during the study (baseline, and after a 3-year period) an HRQoL (measured by MSQoL-54), EDSS, Hamilton Rating Scale for Depression (HDRS) and Fatigue Severity Scale (FSS) were assessed. At the end of a 3-year follow-up, 12 out of 109 patients (11%) had dropped out. Multiple linear regression analysis showed that Physical Health scale of MSQoL-54 is significant independent predictor of change in EDSS after 3 years (p = 0.035). Mental health composite score of MSQoL-54 was predictor of change in HDRS score (p = 0.049). In separate regression analysis, only social function was independent predictor of the development of depression (p = 0.041). None of the HRQoL domains had predictive effect on the change of FSS. Our study suggests that baseline HRQoL scores, measured by MSQoL-54, could be applied as a prognostic marker for progression of both, disability, and severity of depressive symptoms in MS.

Expression of Th1 and Th17 cytokines and transcription factors in multiple sclerosis patients: does baseline T-bet mRNA predict the response to interferon-beta treatment?

We studied the effect of one-year interferon (IFN)-beta treatment on the in vivo mRNA expression of IFN-gamma, interleukin (IL)-17, T-bet and RoR-gammat, on peripheral blood mononuclear cells (PBMC) from 36 multiple sclerosis (MS) patients. In the total MS group, IFN-beta induced decrease in mRNA levels of IFN-gamma and T-bet (p<0.0001), while the levels of IL-17 and RoR-gammat remained similar. In both responders and non-responders, IFN-beta induced significant decrease of IFN-gamma (p<0.0001 and p=0.011, respectively), while decrease in T-bet was detected only in responders (p<0.0001). Higher pre-treatment T-bet allowed prediction of the clinical response in the first year (beta=0.601, p=0.036). Our preliminary findings suggest that T-bet expression might be a potential prognostic marker of treatment response to IFN-beta in MS.

Survival of Huntington's disease patients in Serbia: longer survival in female patients.

The objective of this study was to estimate probability of survival of Huntington's disease (HD) patients in Serbia as a function of CAG repeat length and selected demographic variables. This follow-up study was carried out at the Institute of Neurology, Clinical Centre of Serbia, Belgrade, 1982-2004. The study group consisted of 112 HD patients. The significant inverse correlation was found between CAG repeat length and age at onset of HD (r = -0.732, P = 0.001) and age at death (r = -0.760, P = 0.001). The cumulative probabilities of survival in a five, ten, fifteen, and twenty-years' period were 90.9, 63.2, 10.3 and 4.5%, respectively. Higher survival probabilities were registered in female patients, as well as in those with older age at onset and lower number of CAG repeat length (

[Acute sciatic neuropathy--"post-Saturday palsy"].

This is a case report of 25-year old, unemployed male, admitted to hospital due to acute onset of the left foot drop, subsequent walking difficulty and numbness of the left calf and foot. Symptoms began after prolonged sleep with previous heroin abuse by sniffing. During neurological examination, mild weakness of knee flexors, moderate weakness of plantar flexors and paralysis of foot dorsiflexors, together with hypesthesia of the left calf, foot and fingers, predominantly in the innervation area of common peroneal nerve on the same side, were observed. The electrophysiologic examination revealed predominant involvement of peroneal division within the sciatic nerve, together with recorded conduction block indicating the compression as possible mechanism of nerve injury. The patient was administered corticosteroid therapy during two months, what resulted in almost complete recovery. The peculiarity of this case report is in the presence of the sciatic nerve "Saturday night palsy" with possible effect of former heroin abuse.