Michael J. Aminoff

Status epilepticus: Causes, clinical features and consequences in 98 patients

The etiology, clinical features and outcome of generalized major motor status epilepticus in 98 patients over the age of 14 years have been reviewed. Approximately half of the patients had not had previous seizures. The most common single cause of the status was noncompliance with anticonvulsant drug regimens and this accounted for the status in 53 percent of the patients with previous seizures and in 28 percent of all the patients in our series. The other causes in our series were alcohol-withdrawal, cerebrovascular disease, cerebral tumors or trauma (involving especially the frontal lobe), intracranial infection, metabolic disorders, drug overdose and cardiac arrest. In 15 percent of the patients, however, no specific cause could be found. Status was never the initial manifestation of primary (constitutional) generalized epilepsy in our experience. The etiology of the status was sometime multifactorial, so patients must be screened as fully as possible even when a likely cause is readily apparent. The motor manifestations of the convulsions were frequently restricted in distribution (62 percent of the cases). Focal or lateralized convulsive activity, especially during the course of continued seizure activity, did not necessarily indicate that localized structural pathology was responsible for the status. The seizures were of the tonic variety in a few of our patients and in such circumstances were usually associated with cerebral anoxia. We found that a poor outcome of the status was more likely as its duration increased, and the morbidity rate from the status itself was 12.5 percent among our patients, with a mortality rate of 2.5 percent. The episode of status was usually accompanied by hyperthermia, and often by a brisk peripheral leukocytosis, and in some of our patients a status-induced cerebrospinal fluid pleocytosis also developed. These features may lead to diagnostic confusion if their basis is not recognized. In most of our patients a systemic acidosis developed during the course of the status, but this did not appear to greatly influence the outcome.

Results from a phase I safety trial of hAADC gene therapy for Parkinson disease

Background: In a primate model of Parkinson disease (PD), intrastriatal infusion of an adeno-associated viral (AAV) vector containing the human aromatic l-amino acid decarboxylase (hAADC) gene results in robust gene expression. After gene transfer, low doses of systemically administered l-dopa are converted to dopamine in the transduced striatal neurons, resulting in behavioral improvement without the side effects typically associated with higher doses of l-dopa. These studies led to the initiation of a phase I safety trial. Here we report the findings for the first cohort of five patients. Methods: Patients with moderate to advanced PD received bilateral infusion of a low dose of the AAV-hAADC vector into the putamen. PET scans using the AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), were performed at baseline and at 1 and 6 months after infusion as an in vivo measure of gene expression. Results: PET results showed an average 30% increase in FMT uptake (Kic) in the putamen after gene transfer. Preliminary analysis of clinical data indicates a modest improvement, but absence of a control and the nonblinded analyses make interpretation difficult. Conclusions: Thus far, this gene therapy approach has been well tolerated and shows PET evidence of sustained gene expression. These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit. GLOSSARY: AADC = aromatic l-amino acid decarboxylase; AAV = adeno-associated viral; DA = dopamine; FMT =6-[18F]fluoro-l-m-tyrosine; hAADC = human aromatic l-amino acid decarboxylase; l-dopa = levodopa; PD = Parkinson disease; ROI = region of interest; UPDRS = Unified Parkinson’s Disease Rating Scale.

Recommendations for the clinical use of somatosensory-evoked potentials.

The International Federation of Clinical Neurophysiology (IFCN) is in the process of updating its Recommendations for clinical practice published in 1999. These new recommendations dedicated to somatosensory-evoked potentials (SEPs) update the methodological aspects and general clinical applications of standard SEPs, and introduce new sections dedicated to the anatomical-functional organization of the somatosensory system and to special clinical applications, such as intraoperative monitoring, recordings in the intensive care unit, pain-related evoked potentials, and trigeminal and pudendal SEPs. Standard SEPs have gained an established role in the health system, and the special clinical applications we describe here are drawing increasing interest. However, to prove clinically useful each of them requires a dedicated knowledge, both technical and pathophysiological. In this article we give technical advice, report normative values, and discuss clinical applications.

The pathophysiology of spinal vascular malformations

Abstract The neurological syndrome that occurs most commonly in patients with a spinal angioma is gradual in onset, but progresses steadily until there is clinical evidence of an extensive lesion in both longitudinal and transverse axes of the spinal cord. The pathophysiological basis of this is difficult to account for by prevailing theories. We suggest that there is a reduced arteriovenous pressure gradient due to an increase in venous pressure resulting from the anomalous shunt; this, in turn, leads to a reduced intramedullary blood flow, and thus to ischaemic hypoxia. This theory provides an explanation of many of the previously ill-understood clinical and pathological features of these patients. It receives corroborative support from the pathological findings we describe in a case of spinal angioma.

Safety and tolerability of putaminal AADC gene therapy for Parkinson disease

Background: In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial. Methods: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [18F]fluoro-l-m-tyrosine (FMT) were performed as a measure of gene expression. Results: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased “on” time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort. Conclusion: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson’s Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

AAEM Minimonograph 32: The electrodiagnostic examination in patients with radiculopathies

The anatomy and pathophysiology of radiculopathies are reviewed, and the electrodiagnostic approaches used in evaluating patients with suspected root lesions are discussed. Such electrophysiologic procedures include motor and sensory nerve conduction studies, late‐response studies, somatosensory and motor evoked potentials, nerve root stimulation, and needle electromyography. The value and limitations of these different procedures are considered. At the present time, needle electromyography is the single most useful approach. The findings in patients with radiculopathies at different levels are summarized. Muscle Nerve 21: 1612–1631, 1998

Evaluation of thermography in the diagnosis of selected entrapment neuropathies

We studied 20 normal subjects, 22 patients with carpal tunnel syndrome, and 15 with ulnar neuropathy at the elbow to compare the diagnostic accuracy of infrared thermography with that of conventional electrodiagnostic studies. We found abnormal thermograms in 55% of patients with carpal tunnel syndrome and 47% with ulnar neuropathy, using 2.5 SD from the normal mean as criteria for abnormality. The abnormalities consisted of either an increase in interside temperature difference in the fingers and hands or an alteration of the normal thenar-hypothenar temperature gradient in the fingers. The sensitivity of thermography was considerably lower than that of conventional electrodiagnostic methods. Moreover, the thermographic abnormalities were nonspecific, and could be misleading as they did not reliably identify the side of lesion or distinguish between median or ulnar nerve involvement. Thus, thermography is not helpful in the diagnosis of these two common entrapment neuropathies.

Controlled trial of botulinum toxin injections in the treatment of spasmodic torticollis

We administered local injections of botulinum toxin to 20 patients with torticollis in a blinded, placebo-controlled study. Each patient received four sets of injections: three different doses of botulinum toxin and one placebo. The order of the sessions was random and unknown to the patients. Sixteen of the patients (80%) reported subjective improvement to at least one dose of botulinum toxin; 11 (55%) reported substantial improvement. No objective benefit was documented. Side effects were minor and transient, although dysphagia occurred in four. Some patients reported that the effect waned despite persistent relaxation or even flaccidity of previously overactive muscles, suggesting a change in the pattern of muscle activity after botulinum toxin injections.

IFCN recommended standards for short latency somatosensory evoked potentials. Report of an IFCN committee

Short latency somatosensory evoked potentials (SEPs) are the electrical potentials generated mainly by the large fiber sensory pathways in the peripheral and central portions of the nervous system. SEPs can be elicited from almost any large nerve, although the median and posterior tibial nerves are usually chosen. The short latency responses occur within the first 50 msec after a brief stimulus. Other later middle latency and long latency SEPs also occur, but with a wider range of normal variability making clinical use more difficult. The recommended standards set out below address specifically the short latency median and posterior tibial nerve SEPs. Analogous standards should be applied for testing other nerves such as ulnar or peroneal. The literature contains many reports using techniques that differ from those described here. The peaks, latencies, amplitudes and normal limits in those reports will not necessarily correspond to results described here. Age has a significant effect on the SEP. In young children, the N9 and N13 potentials occur quite early, and the central conduction is relatively slow. Among older adults, normal limits for most latencies are longer by 5-10%, most of this change occurring after age 55 years. Similar changes occur for posterior tibial nerve SEPs. The patients limbs should be kept warmed during testing, since cool limb temperatures can slow the peripheral conduction. Peak latencies are significantly correlated with height, whereas interpeak latencies are affected less. Most medications have little effect on these potentials, and so sedation with a benzodiazepine or similar medication may be employed to aid the subject relaxation. Sleep may change the apparent median nerve N20 latency by increasing the amplitude of a peak component slightly later than that used for scoring for testing during wakefulness. This may cause a slight latency asymmetry to appear when one limb is tested with the patient awake and the other with the patient asleep.