Neurological Disorders

“The patient, a forty-two-year-old drug addict, sat frozen and mute, looking more like a mannequin than a man…” So begins Dr. J. William Langston his wonderful story called ‘The Case of the Tainted Heroin’ [1]. Dr. Langston also added an illustrative subtitle: ‘a Trail of Tragedies Leads to a New Theory of Parkinson’s Disease’. What the author recounts in this scientific article (and posteriorly in a book called ‘The Case of the Frozen Addicts’ [2]) is the story of a number of heroin abusers who presented at different emergency rooms with indistinguishable symptoms from those of Parkinson’s disease (PD) and the common thread that all of them self-administered ‘synthetic’ heroin contaminated with a meperidine analogue: MPTP . Although 6-OHDA was firstly used to lesion the nigrostriatal dopaminergic system in the rat [3] and to model parkinsonism, the discovery of MPTP as a dopaminergic neurotoxin in the brain (first in humans; then in non-human primates and several rodent species) opened a new era in the use of animals to study PD.

Cerebral amyloid angiopathy (CAA) occurs sporadically in elderly populations or in familial forms of Alzheimer’s disease (AD) and is characterized by insoluble deposition of amyloid-beta peptides (Aβ), within arterial vessels of the central nervous system. Amyloid precursor protein is processed by β- and γ-secretases generating Aβ1-40 and Aβ1-42 species that exist as soluble monomers, soluble oligomers (toxic intermediate species), and insoluble fibrils (principle component of CAA) [1]. Of interest, the co-morbidity and relationship between vascular compromise and neurodegenerative processes are not fully understood. CAA is an associated risk factor for intracerebral hemorrhage and ischemic stroke and also may contribute to the cognitive decline observed in aging, AD, or both [1]. Most AD cases feature early decreases in cerebral perfusion that may arise as a consequence of peripheral vascular disease (e.g., type II diabetes, hypertension) and/or loss of basalocortical cholinergic innervation that regulates cerebral blood flow (CBF) among other neurological functions [2]. Much remains to be understood concerning CAA-induced vasomotor impairment and its impact toward the occurrence and/or progression of impaired cognitive function within neurodegenerative disease.

Abstract

Patient candidacy for acute stroke intervention, is currently assessed using brain computed tomography angiography (CTA) evidence of significant stenosis/occlusion (SSO) with a high National Institutes of Health Stroke Scale (NIHSS) (>6). This study examined the association between CTA without significant stenosis/occlusion (NSSO) and lower NIHSS (≤ 6) with transient ischemic attack (TIA) and other good clinical outcomes at discharge. Patients presenting <8 hours from stroke symptom onset, had an NIHSS assessment and brain CTA performed at presentation. Good clinical outcomes were defined as: discharge diagnosis of TIA, modified Rankin Score [mRS] ≤ 1, and home as the discharge disposition. Eighty-five patients received both an NIHSS at presentation and a CTA at 4.2 ± 2.2 hours from stroke symptom onset. Patients with NSSO on CTA as well as those with NIHSS≤6 had better outcomes at discharge (p<0.001). NIHSS ≤ 6 were more likely than NSSO (p=0.01) to have a discharge diagnosis of TIA (p<0.001). NSSO on CTA and NIHSS ≤ 6 also correlated with fewer deaths (p<0.001). Multivariable analyses showed NSSO on CTA (Adjusted OR: 5.8 95% CI: 1.2- 27.0, p=0.03) independently predicted the discharge diagnosis of TIA. Addition of NIHSS ≤ 6 to NSSO on CTA proved to be a stronger independent predictor of TIA (Adjusted OR 18.7 95% CI: 3.5-98.9, p=0.001).

Background: Intracerebral hemorrhage is associated with poor clinical outcome and high mortality. Research and treatment modalities have focused on the expansion of the primary hematoma through blood pressure control and activation of coagulation factors. However, clinical trials have failed to show decreased rates of death or disability in intracerebral hemorrhage following hospital initiation of blood pressure control. However, as clinical deterioration often occurs immediately after onset, pre-hospital initiation of blood pressure control may be more ideal.

Methods: Relevant terms in the National Library of Medicine PubMed database and selected research including basic science, translational reports, meta-analyses, and clinical studies were searched.

Results: Trends indicating improved clinical outcome in intracerebral hemorrhage after hospital-initiated intensive systolic blood pressure control (goal<140 mmHg) have been demonstrated. Statistical significance may not have been obtained because of late treatment times of blood pressure control that approached median 4-6 hours after clinical onset. One trial utilizing glyceryl trinitrate in the pre-hospital setting has been shown to significantly decrease blood pressure within fifteen minutes and improve 90-day clinical outcome.

Conclusions: Glyceryl trinitrate represents an ideal pre-hospital blood pressure medication because it can be delivered via sublingual or transdermal routes, has a quick and graded onset of action, has neuroprotective effects, maintains cerebral perfusion, and has an established record of safety. As intracerebral hemorrhage requires prompt action to prevent clinical deterioration, more emphasis on pre-hospital therapies for blood pressure reduction will become essential in future therapies.

Abstract

Background: Genetic risk factors play an important role in neurological disorders. In this case-control study, we examined the C677T polymorphism (rs1801133) in the Methylenetetrahydrofolate reductase (MTHFR) gene and its association with three neurodegenerative disorders: The late onset pathology, Alzheimer disease and two early onset ones, Autism and Down syndrome. New evidence suggests that autism may be associated with varied behavioural responses to folate therapy and metabolic anomalies, including those in folate metabolism, that contribute to hypomethylation of DNA. We hypothesis that, MTHFR C677T mutation may be the underlying common risk factor in various neurological disorders leading to impaired one carbon metabolism resulting in similar and severe neuropsychological symptoms. Hence our objective was to evaluate MTHFR C677T polymorphism in different Neurological disorders and compare it with age-matched healthy controls.

Method: This case-control study was carried out on 200 samples which included 100 patients with different neurological disorders and 100 healthy individuals without any neurological problems taken as the control group. MTHFR polymorphism was assessed by PCR-RFLP.

Results: Results indicated that the C677T MTHFR polymorphism was not significantly different between controls of younger and older age groups. Among the three neurological disorders studied the T allele was associated with autism (TT+CT vs. CC; OR=4.472, 95% CI: 1.605-12.799, p<0.002), but not with the other two conditions.

Conclusion: In conclusion, despite the smaller sample size, the C677T polymorphism of MTHFR plays a role in some complex neurodevelopmental disorders and not in others.

Abstract Mitochondrial DNA (mtDNA), which encodes components of the mitochondria electron transfer complexes, is highly susceptible to damage produced by reactive oxygen species (ROS), due to its close proximity to ROS generated through the respiratory chain and the paucity of protective histones. Accumulation of mtDNA damages during aging result in the reduced expression of the mitochondria electron transfer complexes, especially complex I. The resultant reduced activity of complex I further increases the generation of ROS, forming a vicious cycle. During aging, the accumulation of oxidative mtDNA damages is prominently found in the brain resident microglia. Increased intracellular ROS, in turn, drives microglia to provoke excessive neuroinflammation in the aged brain through activation of nuclear factor-κB (NF- κB). Hypoxia activates microglia to induce the generation of mitochondria-derived ROS and the subsequent activation of NF-κB signaling pathway to produce pro-inflammatory mediators, which impairs the cognitive functions. Propolis, a resinous substance produced by honeybees, significantly inhibits the hypoxia-induced neuroinflammatory responses by microglia. Furthermore, propolis and Ratanasampil, a traditional Tibetan medicine, improve the cognitive functions of the people who are living at high altitude. Considering that the daily exposure to hypoxia is one of risk factors for the aging-related cognitive impairments, these pharmacological approaches that prevent and reverse “microglia-aging” may become a most promising future research avenue for preventing the aging-related cognitive impairments.

Cervical dystonia (CD) is a focal dystonia affecting cervical muscles leading to abnormal postures and movements of the head, neck and shoulders. Cervical dystonia is a chronic disease with unwanted side effects. Although muscle contractions represent the most visible disease feature, associated symptoms such as pain are frequent and relevant contributors to disability. At the same time, pain constitutesone of the most important factors in term of poor quality of life (QOL) and is one of the most affected QOL domains in CD patients.

However, the mechanism underlying the pain associated with CD remains unclear. There are no therapeutic controlled trials that have evaluated pain or QOL as a primary outcome, but the available data suggest that therapeutic interventions that improve dystonia also alleviate pain and have a beneficial effect on QOL. Recent studies have demonstrated that Electromyography (EMG) biofeedback is a good option for treatment of CD. The main aim of present research was to investigate the effect of EMG biofeedback on pain and health related quality of life of cervical dystonia patients. To do so, a sample of 30 subjects with cervical dystonia was selected for experimental and control groups by an accessible sampling procedure. Subjects were assessed with the pain subscale of Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and the Short-form Health Survey with 36 questions (SF-36) in two stages (pre-test, post-test). The obtained data were analyzed through covariance analysis method. After 30 sessions of EMG biofeedback training, the mean scores of pain in the experimental group were significantly diminished. Also, the mean of SF-36 scores in the experimental group showed a significantly higher increase in comparison to that of the control group. The results suggested that EMG biofeedback was effective on pain and health related QOL of CD patients.

Abstract We report a case of Rasmussen’s Encephalitis. It is a rare, chronic inflammatory neurological disease of unknown origin that usually affects only one hemisphere of the brain. It is common in children under the age of 10 with average age at disease onset around 6 years but uncommon in adults, adult variant that accounts for about 10% of the cases only. Rasmussen’s Encephalitis is characterized by intractable severe seizures, loss of motor skills and speech, paralysis on one side of the body (dysfunctions associated with the affected hemisphere). Our case is a 21 years old female, presented to emergency department JMPC Karachi with complaint of intractable severe seizures, progressive hemiparesis and deteriorated cognition followed by an episode of encephalitis. Her course of illness was focal seizures and right-sided weakness (hemiparesis) for 5 months. In addition to classical clinical presentation of Rasmussen’s Encephalitis, MRI Brain showed hemispheric atrophy of one cerebral hemisphere and old gliotic changes that further supports diagnosis of Rasmussen’s Encephalitis.