CD4 cell count at initiation of ART, long-term likelihood of achieving CD4 >750 cells/mm3 and mortality risk.

OBJECTIVES: We sought to evaluate associations between CD4 at ART initiation (AI), achieving CD4 >750 cells/mm(3) (CD4 >750), long-term immunological recovery and survival. METHODS: This was a prospective observational cohort study. We analysed data from ART-naive patients seen in 1996-2012 and followed ≥3 years after AI. We used Kaplan-Meier (KM) methods and log-rank tests to compare time to achieving CD4 >750 by CD4 at AI (CD4-AI); and Cox regression models and generalized estimating equations to identify factors associated with achieving CD4 >750 and mortality risk. RESULTS: Of 1327 patients, followed for a median of 7.9 years, >85% received ART for ≥75% of follow-up time; 64 died. KM estimates evaluating likelihood of CD4 >750 during 5 years of follow-up, stratified by CD4-AI <50, 50-199, 200-349, 350-499 and 500-750, were 20%, 25%, 56%, 80% and 87%, respectively (log-rank P < 0.001). In adjusted models, CD4-AI ≥200 (versus CD4-AI <200) was associated with achievement of CD4 >750 [adjusted HR (aHR) = 4.77]. Blacks were less likely than whites to achieve CD4 >750 (33% versus 49%, aHR = 0.77). Mortality rates decreased with increasing CD4-AI (P = 0.004 across CD4 strata for AIDS causes and P = 0.009 for non-AIDS death causes). Among decedents with CD4-AI ≥50, 56% of deaths were due to non-AIDS causes. CONCLUSIONS: Higher CD4-AI resulted in greater long-term CD4 gains, likelihood of achieving CD4 >750, longer survival and decreased mortality regardless of cause. Over 80% of persons with CD4-AI ≥350 achieved CD4 >750 by 4 years while 75% of persons with CD4-AI <200 did not. These data confirm the hazards of delayed AI and support early AI.

Antecedent medical diseases in patients with amyotrophic lateral sclerosis. A population-based case-controlled study in Rochester, Minn, 1925 through 1987.

Odds ratios (ORs) were estimated for the prevalence of antecedent endocrine, metabolic, or vascular diseases among 45 patients with amyotrophic lateral sclerosis from the Rochester, Minn, population compared with 90 control subjects matched for sex, year of birth, period of observation, and residence. Hypertension occurred less frequently in male patients with amyotrophic lateral sclerosis (4%) than in control subjects (30%; OR = .10). Because of small population size, no conclusions can be drawn with respect to the following antecedent conditions: thyroid disease (OR = 1.61), coronary artery disease (OR = .58), obesity (OR = .52), diabetes (OR = 1.00), cerebrovascular disease (OR = .21), and peripheral vascular disease (OR = 1.23). The heterogeneity of antecedent thyroid disease makes it highly unlikely that any specific thyroid lesion is causally associated with most cases of amyotrophic lateral sclerosis. Hypertension may be a marker for protective factors against the development of amyotrophic lateral sclerosis in men.

Comparing composite scores based on maximal voluntary isometric contraction and on semiquantitative manual motor testing in measuring limb strength in patients with ALS.

Maximal voluntary isometric contraction (MVIC) is a standardized tool for measuring disease progression in patients with ALS. After normalization, summation, and averaging, it generates composite scores (CS) ("megascores"). In a cross-sectional study, these scores were highly correlated with "average strength" composite scores based on semi-quantitative manual motor testing (SQMMT): r = 0.697 (p < 0.0001). Each 10% difference in the raw SQMMT-CS corresponds to a 0.56 difference in the MVIC-CS (95% confidence limits [CL], 0.38, 0.74). Controlling for height (a highly significant covariate, p < 0.0001), each 10% difference in SQMMT-CS corresponds to a 0.39 difference in MVIC-CS (95% CL, 0.24, 0.54).

Sensorineural hearing loss: a reversible effect of valproic acid.

We report 2 patients over the age of 70 who, while on valproate (VPA) for complex partial seizures, developed sensorineural hearing loss. Following discontinuation of VPA for nonaudiologic reasons, the patients reported improved hearing which was confirmed by audiometry. These findings represent VPA-induced sensorineural hearing loss, possibly in preexisting presbycusis.

How frequently does classic amyotrophic lateral sclerosis develop in survivors of poliomyelitis?

There is a paucity of reports of classic amyotrophic lateral sclerosis (ALS) developing in survivors of paralytic poliomyelitis. We describe a patient with classic ALS and an antecedent paralytic disease thought to have been poliomyelitis from which she recovered completely. If the paucity of ALS preceded by true poliomyelitis is not merely a matter of underreporting, antecedent paralytic poliomyelitis may have a protective role against the development of ALS. This has implications relevant to pathogenesis and to projected secular trends of ALS incidence since the introduction of poliomyelitis vaccines. There is a need to establish the incidence of cases of classic ALS in patients with antecedent poliomyelitis.

Epidemiologic correlates of sporadic amyotrophic lateral sclerosis.

We evaluated 74 selected patients with amyotrophic lateral sclerosis (ALS) and 201 matched controls for risk factors for ALS by a case-control design and a sequential questionnaire/interview technique to quantitate biographic data. We analyzed occupational and recreational data only for 47 male patients and 47 corresponding patient controls; data for women were insufficient. We used nonparametric analyses to evaluate five primary comparisons of ALS patients with controls: (1) more hard physical labor, p not significant (NS); (2) greater frequency of neurodegenerative disease in family members, p NS; (3) greater exposure to lead, p less than 0.05; (4) more years lived in a rural community, p NS; and (5) more trauma or major surgery, p NS. Men with ALS had worked more frequently at blue-collar jobs (although not a statistically significant difference, p = 0.10) and at welding or soldering (p less than 0.01). These results suggest that there may be an association between ALS in men and exposure to lead vapor. The limited nature of the association favors a multifactorial etiologic mechanism of ALS.

When is an apparent excess of neurologic cases epidemiologically significant?

To conserve clinical and public health resources, it is necessary to screen reports from the community of an excess or cluster of cases of chronic neurologic diseases for potential epidemiologic significance, ie, to identify those clusters that may have occurred owing to the operation of an underlying etiologic cause rather than to chance alone. Traditionally, the probability that such a cluster has occurred by chance within the reporting community is computed, ignoring the fact that many other similar communities have not reported a cluster. We propose a modified approach that takes this larger universe of communities into account, thereby raising the threshold for potential epidemiologic significance. As a result, the lowest value for the ratio of observed-to-expected cases that may be considered of epidemiologic significance should be increased by factors of 2 for small clusters (one to three expected cases), 1.5 for intermediate clusters (seven to 30 expected cases), and 1.3 for large clusters (60 to 90 expected cases). Consequently, case ascertainment and full field investigations can be reserved for only those reports that, if confirmed, would represent a cluster not due to chance alone. We illustrate this with a case from our own experience.

Reversible parkinsonism and cognitive impairment with chronic valproate use.

Following our initial report of the insidious development of reversible, valproate-induced hearing, motor, and cognitive dysfunction in two patients, we evaluated 36 patients in an epilepsy clinic who had been taking therapeutic levels of valproate for at least 12 months; 29 of these patients were examined according to a prospective protocol. We observed varying degrees of parkinsonism and cognitive impairment, from none to severe. Discontinuation of valproate in 32 affected patients led to subjective and objective improvement on follow-up testing at least 3 months later. Improvement was greatest in patients who were affected most. We conclude that a syndrome of reversible parkinsonism and cognitive impairment may develop insidiously in patients who have been treated with valproate for more than 12 months. The association with valproate may be overlooked due to the insidious onset.

Seizure onset from periventricular nodular heterotopias: depth-electrode study.

The association between gray matter heterotopias and seizures is well established; whether seizures originate from these lesions is not known. We evaluated three patients with intractable complex partial seizures and periventricular nodular heterotopias (PNHs) with video-EEG monitoring with multiple depth electrodes, including placement in the PNH, to determine whether seizures originate from the PNH. In two of the three patients, all seizures arose from the PNH as low-voltage beta activity. In the third patient, 80% arose from the hippocampi and 20% from the heterotopia. PNHs may serve as an epileptogenic focus in patients with intractable epilepsy.

Relationship of the Tufts Quantitative Neuromuscular Exam (TQNE) and the Sickness Impact Profile (SIP) in measuring progression of ALS. SSNJV/CNTF ALS Study Group.

The Tufts Quantitative Neuromuscular Exam (TQNE) is a standardized tool for measuring muscle strength and pulmonary function in patients with amyotrophic lateral sclerosis (ALS). We describe the relationship of TQNE scores to functional disability and health-related quality of life as measured by the Sickness Impact Profile (SIP) in 524 ALS patients. There was a significant relationship (p < 0.0001) between TQNE and SIP scores, both in cross section and over time. TQNE scores strongly relate to ALS patients' quality of life and ability to perform activities of daily living.

Toward earlier diagnosis of amyotrophic lateral sclerosis: revised criteria. rhCNTF ALS Study Group.

We modified the World Federation of Neurology (WFN) diagnostic criteria for ALS to facilitate early diagnosis and used these criteria for enrollment of ALS patients in a clinical trial. The criteria developed required lower motor neuron (LMN) involvement in at least two limbs and upper motor neuron involvement in at least one region (bulbar, cervical, or lumbosacral). The EMG finding of fibrillation potentials was required for evidence of LMN involvement. Electrodiagnostic studies, neuroimaging, and laboratory studies were also used to exclude disorders that might mimic ALS. Using these criteria, the diagnosis of ALS was made at a mean time of 9.7 months from onset of symptoms, which compares favorably with the 12-month period cited in the literature. Using clinical assessment at completion of the trial, the diagnosis of ALS was believed to be accurate in those patients entered in the trial. However, pathologic confirmation of the diagnosis of ALS was not obtained. Based on our preliminary experience, we propose that these ALS diagnostic criteria will facilitate early diagnosis of ALS. Future studies should prospectively compare these criteria with the WFN criteria currently in use.

Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group.

We designed a phase II trial to evaluate the efficacy of gabapentin in slowing the rate of decline in muscle strength of patients with amyotrophic lateral sclerosis (ALS) and to assess safety and tolerability. Gabapentin (800 mg) or placebo was administered t.i.d. in a randomized, double-blinded, placebo-controlled, trial for 6 months. We enrolled 152 patients at eight sites in the United States. The primary outcome measure was the slope of the arm megascore, the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population. A secondary outcome measure was forced vital capacity. Slopes of arm megascores for patients on gabapentin were compared with slopes of those taking placebo using a two-way ANOVA. We observed a nonstatistically significant trend (p = 0.057-0.08) toward slower decline of arm strength in patients taking gabapentin compared with those taking placebo (mean difference 24%, median 37%). We observed no treatment effect on forced vital capacity. Gabapentin was well tolerated by patients with ALS. These results suggest that further studies of gabapentin in ALS are warranted.

Clinical neurophysiologic studies in stiff-man syndrome: use of simultaneous video-electroencephalographic-surface electromyographic recording.

Three patients with a clinical diagnosis of stiff-man syndrome were studied with simultaneous video-electroencephalographic-surface electromyographic recordings in addition to routine electromyography in order to obtain objective data to confirm their diagnosis, to improve our understanding of the diagnosis of stiff-man syndrome, and to define reproducible clinical and neurophysiologic criteria for the stiff-man syndrome. These patients had the following features of this syndrome: (1) continuous muscle activity that varied with awake and sleep states, posture, passive and active movements, and medications; (2) superimposed intermittent generalized contractions while awake, which continued into drowsiness and interfered with onset of sleep; and (3) abnormal cocontractions of antagonistic muscles. The characteristic findings in the stiff-man syndrome can be recorded by using video-electroencephalographic-surface electromyographic techniques, a useful application of equipment already available in most electroencephalography laboratories. Neurophysiologic techniques can help in elucidating the clinical findings in the stiff-man syndrome. Further systematic study in patients before and during treatment is needed to identify common diagnostic criteria for this syndrome.

Hyperbaric treatment of cerebral air embolism sustained during an open-heart surgical procedure.

A case of cerebral air embolism sustained during replacement of the mitral valve resulted in postoperative coma and seizures. Hyperbaric treatment, begun 30 hours after the occurrence of the air embolism, resulted in good immediate and long-term recovery. Mild deficits of the left hemisphere were present at follow-up 53 days after the embolus was sustained, and lesser, minimal residua were present at 14-month follow-up. Hyperbaric treatment is the definitive therapy for cerebral air embolism. Although it is most effective when administered early, the outcome may be excellent even with late treatment.

Linear estimates of rates of disease progression as predictors of survival in patients with ALS entering clinical trials.

Maximal voluntary isometric grip and foot dorsiflexion (FD) strength and forced vital capacity (FVC) were obtained in 62 patients with ALS at or close to enrollment into two clinical trials. The agents tested did not slow disease progression. Isometric strength data were standardized, and the worse side was taken. FVC was expressed as a percentage of the predicted value (FVC%). We derived linear estimates of rates of disease progression based on the isometric myometry and FVC measures and on disease duration. Forty one patients were known to have died or to have undergone tracheostomy for ventilatory support. Probability of tracheostomy-free survival was calculated using the Kaplan-Meier method. The measured values, the linear estimates for rates of decline of these values, gender, age at onset, bulbar vs. spinal onset, height and weight were tested as risk factors within the Cox proportional hazards model, using regression techniques. When tested individually, estimates of rates of decline based on all three measures (FD, grip and FVC%) were the only statistically significant risk factors (P<0.005). Multivariate analysis resulted in a 3-variable model (chi-square=75.3, P<0.00001) in which estimated rates of decline of FD strength and of FVC%, and bulbar onset were independently significant (P<0.0001, P<0.0007 and P<0.05, respectively). We conclude that linear estimates of the rate of disease progression till enrollment into a clinical trial may be better predictors of patient survival than demographic data or discrete biologic measures.

Mechanical trauma as a risk factor in classic amyotrophic lateral sclerosis: lack of epidemiologic evidence.

We have examined the relationship between mechanical injuries and the subsequent development of classic amyotrophic lateral sclerosis (ALS) through a critical review of the literature. Only prospective evaluation of a large cohort of trauma victims can provide an unbiased answer to this controversy. However, such an evaluation would be prohibitively expensive, and the results would not be available in our lifetime. The results of retrospective case-control studies are conflicting in part because of biases in the selection of patients and controls, poor definition of the nature and extent of the trauma and its chronological relationship to the onset of ALS, and a non-uniform approach to the collection of antecedent information. More rigorously designed studies show no association of ALS to antecedent trauma. The existing data thus do not suggest that mechanical trauma is a risk factor for ALS. Future case-control studies should conform to a standardized methodology. The critical analysis presented here of the research on the purported connection between mechanical injury and ALS may serve as a model for the evaluation of the role of trauma in other chronic diseases. Application of these methodological principles may bring increased scientific rigor to assessing the frequently litigated question of what constitutes a true trauma sequela.

A brief quality-of-life measure for ALS clinical trials based on a subset of items from the sickness impact profile. The Syntex-Synergen ALS/CNTF Study Group.

We previously demonstrated a significant relationship (P<0.0001) between maximum voluntary isometric contraction (MVC) plus pulmonary function scores (the Tufts Quantitative Neuromuscular Exam Combination Megascore (TQNE CM)), and the Sickness Impact Profile (SIP) in a cohort of 524 ALS patients. Because the 136-item SIP questionnaire can be difficult to administer in this population, we examined SIP subscales and clinically derived item sets in relation to the TQNE CM in an effort to define a briefer measure of quality of life for use in clinical trials. Two 'Mini-SIP' indices performed as well as the overall SIP in reflecting the impact of muscle weakness on ALS patients' quality of life: a combination of two SIP subscales ('SIP-33'), and a 19-item set of questions independently chosen by a panel of ALS specialists ('SIP/ALS-19'). Either index potentially could be useful in ALS clinical trials. The SIP/ALS-19 is currently being used in a National ALS data base, providing an opportunity to evaluate its utility prospectively against other QOL measures in ALS patients.

Alzheimer's disease underlies some cases of complex partial status epilepticus.

Alzheimer's disease is a known risk factor for seizures, and age older than 60 years is a recognized risk factor for poor outcome from convulsive and nonconvulsive status epilepticus. The authors suspect that there may be a causal relationship between dementia pathology and the development and maintenance of refractory seizures. They report two selected patients with complex partial status epilepticus whose presentation and clinical course provide partial support for this hypothesis. Their methods include case reports with clinical, EEG, imaging, and pathologic correlations. The patients were 70 and 85 years of age. Both had central and peripheral brain atrophy on imaging studies (with some regions that were affected more than others), left temporal seizure foci corresponding to areas of greatest cortical atrophy, and early presentation with inhibitory epileptic symptoms (aphasia), with evolution to complex partial status epilepticus. Pathologic confirmation of Alzheimer's disease was obtained in one patient who had not been diagnosed previously. It involved maximally the cortex underlying the seizure focus. A diagnosis of probable Alzheimer's disease was established in the other patient. Alzheimer's disease may be causal in some cases of complex partial status epilepticus. Additional observations in support of this hypothesis are needed.

Evidence-based guideline update: intraoperative spinal monitoring with somatosensory and transcranial electrical motor evoked potentials: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Clinical Neurophysiology Society.

OBJECTIVE: To evaluate whether spinal cord intraoperative monitoring (IOM) with somatosensory and transcranial electrical motor evoked potentials (EPs) predicts adverse surgical outcomes. METHODS: A panel of experts reviewed the results of a comprehensive literature search and identified published studies relevant to the clinical question. These studies were classified according to the evidence-based methodology of the American Academy of Neurology. Objective outcomes of postoperative onset of paraparesis, paraplegia, and quadriplegia were used because no randomized or masked studies were available. RESULTS AND RECOMMENDATIONS: Four Class I and 8 Class II studies met inclusion criteria for analysis. The 4 Class I studies and 7 of the 8 Class II studies reached significance in showing that paraparesis, paraplegia, and quadriplegia occurred in the IOM patients with EP changes compared with the IOM group without EP changes. All studies were consistent in showing all occurrences of paraparesis, paraplegia, and quadriplegia in the IOM patients with EP changes, with no occurrences of paraparesis, paraplegia, and quadriplegia in patients without EP changes. In the Class I studies, 16%-40% of the IOM patients with EP changes developed postoperative-onset paraparesis, paraplegia, or quadriplegia. IOM is established as effective to predict an increased risk of the adverse outcomes of paraparesis, paraplegia, and quadriplegia in spinal surgery (4 Class I and 7 Class II studies). Surgeons and other members of the operating team should be alerted to the increased risk of severe adverse neurologic outcomes in patients with important IOM changes (Level A).