Progressive encephalomyelitis with rigidity and myoclonus: glycine and NMDA receptor antibodies.

BACKGROUND: The syndrome of progressive encephalopathy with limb rigidity has been historically termed progressive encephalomyelitis with rigidity and myoclonus (PERM) or stiff-person syndrome plus. METHODS: The case is presented of a previously healthy 28-year-old man with a rapidly fatal form of PERM developing over 2 months. RESULTS: Serum antibodies to both NMDA receptors (NMDAR) and glycine receptors (GlyR) were detected postmortem, and examination of the brain confirmed an autoimmune encephalomyelitis, with particular involvement of hippocampal pyramidal and cerebellar Purkinje cells and relative sparing of the neocortex. No evidence for an underlying systemic neoplasm was found. CONCLUSION: This case displayed not only the clinical features of PERM, previously associated with GlyR antibodies, but also some of the features associated with NMDAR antibodies. This unusual combination of antibodies may be responsible for the particularly progressive course and sudden death.

A resistant case of spontaneous intracranial hypotension.

The case of a 39-year-old with intractable spontaneous intracranial hypotension (SIH) is presented. He developed bilateral and symptomatic subdural hygromas that were drained in response to clinical deterioration, but proved ineffective. An initial MRI of the lumbar region suggested a lumbosacral CSF leak, but he failed to respond to local blood patching. Subsequent CT myelography revealed a thoracic dural leak and a second directed blood patch proved effective. The aetiology, pitfalls and management of SIH are summarized.

Hemispace differences in the visual perception of size in left hemiParkinson's disease.

The visual perception of size in different regions of external space was studied in Parkinson's disease (PD). A group of patients with worse left-sided symptoms (LPD) was compared with a group with worse right-sided symptoms (RPD) and with a group of age-matched controls on judgements of the relative height or width of two rectangles presented in different regions of external space. The relevant dimension of one rectangle (the 'standard') was held constant, while that of the other (the 'variable') was varied in a method of constant stimuli. The point of subjective equality (PSE) of rectangle width or height was obtained by probit analysis as the mean of the resulting psychometric function. When the standard was in left space, the PSE of the LPD group occurred when the variable was smaller, and when the standard was in right space, when the variable was larger. Similarly, when the standard rectangle was presented in upper space, and the variable in lower space, the PSE occurred when the variable was smaller, an effect which was similar in both left and right spaces. In all these experiments, the PSEs for both the controls and the RPD group did not differ significantly, and were close to a physical match, and the slopes of the psychometric functions were steeper in the controls than the patients, though not significantly so. The data suggest that objects appear smaller in the left and upper visual spaces in LPD, probably because of right hemisphere impairment.

Dopamine and the representation of the upper visual field: evidence from vertical bisection errors in unilateral Parkinson's disease.

It has been suggested that dopamine is an important neurotransmitter in the brain mechanisms which represent the upper visual field. This idea was tested with a vertical line bisection task in unilateral Parkinson's disease. Stimuli of a range of lengths were presented on a large screen in three positions (left, centre and right) and at two viewing distances (0.6 and 1.5m). The patients, who were compared with a group of normal age-matched controls, comprised 16 sufferers from predominantly unilateral disease, 8 with more severe left-sided symptoms (LPD) and 8 with more severe right-sided symptoms (RPD). The LPD group consistently set the bisecting cursor below the midpoint of the stimulus lines, and their bisection error became larger as the length of the line increased. In contrast, the controls set the cursor above the midpoint of the line, an error which also increased with line length. The settings of the RPD group were similar to those of the controls. The results suggest altitudinal neglect in left unilateral PD, and support the hypothesis of dopaminergic involvement in the coding of upper visual space, with the proviso that the perceptual component of this involves the right hemisphere in humans.

Mapping motor cortex projections to single motor units in humans with transcranial magnetic stimulation.

We devised a method to investigate the cortical organization of corticomotoneurons (CMs) to upper limb muscles. A spike-triggering technique was used, in which a tonically discharging single motor unit (SMU) triggered transcranial magnetic stimulation (TMS) of motor cortex, and the probability of producing short-latency discharges (primary excitatory responses [PERs]) was measured. PER probabilities were mapped in 34 SMUs, using a 16 cm(2) scalp grid with the central reference point having a probability of 0.5. Maps showed a single optimum point of scalp stimulation and significant decreases in PER probability with shifts of 2 cm from this point, for all subjects. These findings suggest that the colony of CMs projecting to an individual SMN is contained within a small volume of motor cortex. Changes in PER probability with shifts in stimulation site may reflect the organization of other intracortical neurons mediating TMS activation of these CMs.

Changes in motor evoked potentials to short-interval paired transcranial magnetic stimuli in multiple sclerosis.

OBJECTIVE: Paired transcranial magnetic stimuli (TMS) were applied in 8 multiple sclerosis (MS) patients with asymmetrical clinical signs and in 8 healthy controls to test the hypothesis that the circuits responsible for the generation and transmission of I-waves are abnormal in the former group METHODS: A figure-of-8 coil discharging through a Magstim 200/Bistim configuration delivered identical stimuli at an intensity 10% above the motor threshold of the relaxed first dorsal interosseous muscle. The interstimulus intervals (ISIs) used were varied in a pseudo-randomized fashion in steps of 0.2 ms between 1.0 and 5 ms. RESULTS: In 9 of 12 unilateral studies in the control group, a pattern of 3 peaks of increased motor evoked potential size was found at ISIs of 1.2-1.6 ms, 2.4-3.2 ms and 4.4-5.0 ms. A similar pattern was present in only 5 of 12 studies in the patients (Fisher's exact test, P = 0.1), while it was absent in all the 4 studies of the side with greater clinical involvement in patients (P = 0.01) CONCLUSION: Our results suggest that I-wave generation is more likely to be defective in MS than in normal subjects, that this defect resides in the cortex, and that it correlates with severity of physical signs.

Covariation between human intrinsic hand muscles of the silent periods and compound muscle action potentials evoked by magnetic brain stimulation: evidence for common inhibitory connections.

Transcranial magnetic stimuli at different stimulus intensities were applied in six healthy subjects to test the hypothesis that, in different intrinsic hand muscles, the duration of the resultant cortically evoked silent periods (C-SPs) from each stimulus would be positively correlated between muscles, indicating a common inhibitory mechanism. A figure-of-eight coil discharging through a Magstim 200 stimulator delivered 25 stimuli at each stimulus intensity at a minimum of five intensities ranging from 55% to 160% of the individual resting motor threshold. In each subject, simultaneous surface recordings from pairs of muscles were made from the first dorsal interosseous (FDI), opponents pollicis (OP), abductor pollicis brevis (APB) and abductor digiti minimi (ADM). The C-SP durations within all three muscle pairs tested were highly correlated (P<0.001). The amplitude of the preceding compound-muscle action potentials (CMAPs) was positively correlated between FDI and OP, but not between APB and ADM or FDI and ADM. C-SP duration was linearly related to stimulus intensity, but did not correlate with the latency or amplitude of the preceding CMAP. SPs elicited by peripheral nerve stimuli in pairs of hand muscles did not co-vary significantly. The results provide evidence that inhibitory influences of cortical origin are distributed widely to intrinsic hand muscles. In contrast, covariation of excitatory effects only appears between muscles synergistically involved in a motor task.

Peripheral and central motor conduction in amyotrophic lateral sclerosis.

Conventional peripheral motor conduction studies and transcranial magnetic stimulation (TMS) studies, to measure central motor conduction time (CMCT), to the first dorsal interosseous muscle (FDI) were performed on 65 patients with amyotrophic lateral sclerosis (ALS). The hands of each patient were classified into one of four groups depending on the presence of physical signs of lower motor neurone (LMN) and/or upper motor neurone (UMN) involvement. Statistical analysis was made of the results from patients compared with previously established normal values and with those from a control group of 53 normal subjects. Results between the four groups of patients were compared in order to assess any correlation between neurophysiological findings and physical signs. A reduction in the amplitude of compound muscle action potentials (CMAP), prolongation of distal motor latency (DML) and F wave latency were found in 36%, 34% and 19% of hands respectively. These abnormalities were more common in hands with LMN signs. In nine hands, prolongation of DML occurred in the absence of muscle wasting or weakness. CMCT abnormalities were present in 17% of patients with ALS but did not appear to correlate with physical signs.

Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis.

The pathogenesis of idiopathic amyotrophic lateral sclerosis (ALS) remains unknown, but accumulating evidence suggests a neuroexcitotoxic mechanism may have some credence. Glutamate-induced hyperexcitability of cortical or spinal motoneurons may be expected to manifest itself as a reduced threshold for activation of these structures. We have measured corticomotor threshold to the first dorsal interosseous (FDI) muscles of 48 patients with sporadic ALS using magnetic brain stimulation and have correlated the findings with physical signs of upper and/or lower motor neuron degeneration. We find that if FDI in patients with ALS shows no weakness, wasting, or signs of an upper motor neuron lesion, mean corticomotor threshold is significantly lower than in 102 healthy control FDI muscles (P = 0.02). In contrast, FDI muscles showing signs of lower motor neuron degeneration only or mixed upper and lower motor neuron signs are associated with a raised corticomotor threshold (P = 0.008, P < 0.001, respectively). We conclude that early in ALS, at a time when hand muscle function is normal, corticomotor threshold is reduced and suggest that this may be a manifestation of abnormal excitability of cortical or spinal motoneurons to neurotransmitters, whose action will ultimately lead to cell death.

Corticomotor threshold to magnetic stimulation: normal values and repeatability.

The threshold for corticomotor excitation by magnetic stimuli is a clinically important parameter in the assessment of central motor conduction. Hitherto, arbitrary criteria have been adopted to define threshold and there are few published data using a figure of eight coil. A new method is described in which the highest stimulus intensity evoking responses in the relaxed first dorsal interosseous muscle with a probability of zero [lower threshold (LT)] and the lowest intensity evoking responses with a probability of one [upper threshold (UT)] have been determined. The method, which utilizes a coil located and optimally oriented over hand motor cortex, minimizes the number of stimuli needed. Both LT and UT are normally distributed and are independent of age, gender, and hemisphere. In 102 healthy hands of 55 control subjects 23-84 years of age, mean +/- SD UT was 46.6 +/- 9.4% and LT was 38.0 +/- 8.6% maximum stimulator output. Repeatability estimates indicated an absolute change of more than 13% or 11% in UT or LT respectively in the same individual over 1-3 months was significant at the 5% level.