Keith J. Nagle

Complications of intravenous immune globulin treatment in neurologic disease

Intravenous immune globulin (IVIg) is advocated as a safe treatment for immune-mediated neurologic disease. We reviewed the medical records of 88 patients who were given IVIg for a neurologic illness. Major complications in four patients (4.5%) included congestive heart failure in a patient with polymyositis, hypotension after a recent myocardial infarction, deep venous thrombosis in a bed-bound patient, and acute renal failure with diabetic nephropathy. Other adverse effects included vasomotor symptoms 26, headache 23, rash 5, leukopenia 4, fever 3, neutropenia 1, proteinuria (1.9 g/day) 1, viral syndrome 1, dyspnea 1, and pruritis 1. Fifty-two patients (59%) had some adverse effect of IVIg infusion, most commonly vasomotor symptoms, headaches, fever, or shortness of breath in 40 (45%), which improved with reduced infusion rate or symptomatic medications. Five (6%) had asymptomatic laboratory abnormalities and seven (8%) had other minor adverse effects. Adverse effects led to discontinuation of therapy in 16% and permanent termination of therapy in 10% of patients. There was no mortality or long-term morbidity. Although adverse effects were frequent, serious complications were rare except in patients with heart disease, renal insufficiency, and bed-bound state. NEUROLOGY 1996;47: 674-677

People with chronic low back pain exhibit decreased variability in the timing of their anticipatory postural adjustments

Variability in the constituents of movement is fundamental to adaptive motor performance. A sustained decrease in the variability of anticipatory postural adjustments (APAs) occurs when performing cued arm raises following acute, experimentally induced low back pain (LBP; Moseley & Hodges, 2006). This observation implies that these changes in variability may also be relevant to people with chronic LBP. To confirm that this reduced variability in the timing of APAs is also evident in people with chronic LBP, the authors examined the standard deviations of electromyographic onset latencies from the bilateral internal oblique (IO) and erector spinae muscles (in relation to deltoid muscle onset) when 10 people with chronic LBP and 10 people without LBP performed 75 trials of rapid arm raises. The participants with LBP exhibited significantly less variability of their IO muscle onset latencies, confirming that the decreased variability of postural coordination that is evident following acutely induced LBP is also evident in people with chronic LBP. Thus, people with chronic LBP may be less capable of adapting their APAs to ensure postural stability during movement.

Low back pain associates with altered activity of the cerebral cortex prior to arm movements that require postural adjustment

OBJECTIVE To determine whether low back pain (LBP) associates with altered postural stabilization and concomitant changes in cerebrocortical motor physiology. METHODS Ten participants with LBP and 10 participants without LBP performed self-initiated, voluntary arm raises. Electromyographic onset latencies of the bilateral internal oblique and erector spinae muscles were analyzed relative to that of the deltoid muscle as measures of anticipatory postural adjustments (APAs). Amplitudes of alpha event-related desynchronization (ERD) and of Bereitschaftspotentials (BP) were calculated from scalp electroencephalography as measures of cerebrocortical motor physiology. RESULTS The APA was first evident in the trunk muscles contralateral to the arm raise for both groups. Significant alpha ERD was evident bilaterally at the central and parietal electrodes for participants with LBP but only at the electrodes contralateral and midline to the arm raise for those without LBP. The BP amplitudes negatively correlated with APA onset latencies for participants with (but not for those without) LBP. CONCLUSIONS Cerebrocortical activity becomes altered prior to arm movements requiring APAs for individuals with chronic LBP. SIGNIFICANCE These results support a theoretical model that altered central motor neurophysiology associates with LBP, thereby implying that rehabilitation strategies should address these neuromotor impairments.

Magnesium Sulfate Treatment Reverses Seizure Susceptibility and Decreases Neuroinflammation in a Rat Model of Severe Preeclampsia

Eclampsia, defined as unexplained seizure in a woman with preeclampsia, is a life-threatening complication of pregnancy with unclear etiology. Magnesium sulfate (MgSO4) is the leading eclamptic seizure prophylactic, yet its mechanism of action remains unclear. Here, we hypothesized severe preeclampsia is a state of increased seizure susceptibility due to blood-brain barrier (BBB) disruption and neuroinflammation that lowers seizure threshold. Further, MgSO4 decreases seizure susceptibility by protecting the BBB and preventing neuroinflammation. To model severe preeclampsia, placental ischemia (reduced uteroplacental perfusion pressure; RUPP) was combined with a high cholesterol diet (HC) to cause maternal endothelial dysfunction. RUPP+HC rats developed symptoms associated with severe preeclampsia, including hypertension, oxidative stress, endothelial dysfunction and fetal and placental growth restriction. Seizure threshold was determined by quantifying the amount of pentylenetetrazole (PTZ; mg/kg) required to elicit seizure in RUPP+HC±MgSO4 and compared to normal pregnant controls (n = 6/group; gestational day 20). RUPP+HC rats were more sensitive to PTZ with seizure threshold being ∼65% lower vs. control (12.4±1.7 vs. 36.7±3.9 mg/kg PTZ; p<0.05) that was reversed by MgSO4 (45.7±8.7 mg/kg PTZ; p<0.05 vs. RUPP+HC). BBB permeability to sodium fluorescein, measured in-vivo (n = 5–7/group), was increased in RUPP+HC vs. control rats, with more tracer passing into the brain (15.9±1.0 vs. 12.2±0.3 counts/gram ×1000; p<0.05) and was unaffected by MgSO4 (15.6±1.0 counts/gram ×1000; p<0.05 vs. controls). In addition, RUPP+HC rats were in a state of neuroinflammation, indicated by 35±2% of microglia being active compared to 9±2% in normal pregnancy (p<0.01; n = 3–8/group). MgSO4 treatment reversed neuroinflammation, reducing microglial activation to 6±2% (p<0.01 vs. RUPP+HC). Overall, RUPP+HC rats were in a state of augmented seizure susceptibility potentially due to increased BBB permeability and neuroinflammation. MgSO4 treatment reversed this, increasing seizure threshold and decreasing neuroinflammation, without affecting BBB permeability. Thus, reducing neuroinflammation may be one mechanism by which MgSO4 prevents eclampsia during severe preeclampsia.

The Contribution of Normal Pregnancy to Eclampsia

Eclampsia, clinically defined as unexplained seizure in a woman with preeclampsia, is a life threatening complication unique to the pregnant state. However, a subpopulation of women with seemingly uncomplicated pregnancies experience de novo seizure without preeclamptic signs or symptoms, suggesting pregnancy alone may predispose the brain to seizure. Here, we hypothesized that normal pregnancy lowers seizure threshold and investigated mechanisms by which pregnancy may affect seizure susceptibility, including neuroinflammation and plasticity of gamma-aminobutyric acid type A receptor (GABAAR) subunit expression. Seizure threshold was determined by quantifying the amount of pentylenetetrazole (PTZ) required to elicit electrical seizure in Sprague Dawley rats that were either nonpregnant (Nonpreg, n = 7) or pregnant (Preg; d20, n = 6). Seizure-induced vasogenic edema was also measured. Further, activation of microglia, a measure of neuroinflammation (n = 6-8/group), and GABAAR δ- and γ2-subunit protein expression in the cerebral cortex and hippocampus (n = 6/group) was determined. Seizure threshold was lower in Preg compared to Nonpreg rats (36.7±9.6 vs. 65.0±14.5 mg/kg PTZ; p<0.01) that was associated with greater vasogenic edema formation (78.55±0.11 vs. 78.04±0.19% water; p<0.05). The % of active microglia was similar between groups; however, pregnancy was associated with downregulation of cortical GABAAR-δ and hippocampal GABAAR-γ2 expression. Overall, pregnancy appears to be a state of increased seizure susceptibility that is not due to neuroinflammation, but rather is associated with reduced expression of GABAAR subunits and greater edema. Understanding neurophysiological changes occurring in normal pregnancy could allow for better prevention and management of de novo seizure, including pathologic states such as eclampsia.

Delirium: pathophysiology, recognition, prevention and treatment

Delirium, a clinical syndrome characterized by the acute onset of confusion, indicates that there is a disruption in physiological equilibrium that may lead to death unless quick and appropriate action is taken. Despite its frequent appearance, delirium often goes unrecognized, undetected and untreated, leading to poorer outcomes including longer lengths of hospitalization, persistent deficits in cognitive function and the need for nursing home placement following acute treatment. Prevention and treatment strategies do not need to be complex or expensive, but require well co-ordinated interventions from multiple disciplines including nursing, psychiatry, neurology and primary care, as well as the co-operation and significant effort of family and friends who know the affected individual well.

Pathology of bilateral pulvinar degeneration following long duration status epilepticus

PURPOSE To define the neuropathological findings of pulvinar degeneration seen in long duration status epilepticus. METHODS We review the clinical, radiologic, neurophysiologic, investigational and neuropathological findings on a 27 year old woman who died after 162 days of prolonged refractory status epilepticus. RESULTS Continuous EEG monitoring confirmed recurrent uncontrolled seizure activity bilaterally and independently, most frequent in the right fronto-temporal region. Initial MRI of the brain was normal. Repeat study until on day 127 of admission showed advanced changes, with bilateral pulvinar T2/FLAIR hyperintensities. The autopsy revealed sharply defined, grey, soft, granular nodules in each medial pulvinar nucleus. Microscopically these consisted of sharply defined paucicellular areas with loss of neurons and myelin and with numerous macrophages in their centers, surrounded by reactive astrocytes with relatively spared of axons. The spinal cord at cervical and thoracic levels showed symmetric spongy vacuolation in the central part of the dorsal columns and lateral corticospinal tracts, with mild myelin loss, relatively preserved axons. The pathological lesions found in this case in thepulvinar are somewhat similar to the pathologic lesions described in Wernickes encephalopathy. Those found in the spinal cord of our patient resemble characteristic features of B12 related subacute combined degeneration. CONCLUSION Characteristic pulvinar degeneration may be found as an acquired phenomenon in prolonged refractory status epilepticus. We hypothesize that the neuropathological findings result from an excessive focal metabolic demand, secondary to neuronal network over activation in the setting of prolonged, frequent bi-temporal seizures.

Insomnia as a Presenting Symptom of Sleep-Related Movement Disorders, Hypersomnias and Parasomnias

Insomnia can be considered as a symptom and as a diagnosis. A number of sleep disorders have insomnia as a principle presenting symptom. A careful history is needed to assess for the presence of coexisting sleep disorders in patients complaining of poor sleep quality. In this chapter, we will explore the clinical features of three common neurologically based sleep disorders that may have insomnia as a presenting feature: restless legs syndrome (RLS), narcolepsy with or without cataplexy, and parasomnias. Several medications used to treat insomnia may exacerbate the patient’s RLS and paradoxically worsen their insomnia. Montplaiser drew attention to the severe sleep disruption in persons with narcolepsy; findings included an increased number of awakenings, increased wake time after sleep onset, and increased time in stage I sleep. These findings have been replicated to varying degrees in a number of other studies. Finally, the coexistence of several sleep problems is more often the rule than the exception. Patients with multiple components to their impaired sleep quality are common and each may need to be addressed to optimally help these patients.

Restless Legs Syndrome in Pregnancy

Restless legs syndrome (RLS) is characterized by limb akathisia that is maximal in the evening while at rest and transiently relieved by movement. The prevalence and severity of RLS increase with age. Women older than 65 have an RLS prevalence of 19%, whereas in nonpregnant women younger than 30 years of age it is only 5% (1). However, gestational RLS (gRLS) is strikingly common, with nearly 25% of pregnant women affected (see below). The association of RLS with pregnancy has been noted since the term was first coined by Ekbom in 1945. RLS is a clinical diagnosis. Its four cardinal clinical features were reviewed in Chapter 8. Further details regarding diagnosis are well described by the International RLS Study Group (2,3)