Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group.

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk.

Lateropulsion, pushing and verticality perception in hemisphere stroke: a causal relationship?

The relationships between perception of verticality by different sensory modalities, lateropulsion and pushing behaviour and lesion location were investigated in 86 patients with a first stroke. Participants sat restrained in a drum-like framework facing along the axis of rotation. They gave estimates of their subjective postural vertical by signalling the point of feeling upright during slow drum rotation which tilted them rightwards-leftwards. The subjective visual vertical was indicated by setting a line to upright on a computer screen. The haptic vertical was assessed in darkness by manually setting a rod to the upright. Normal estimates ranged from -2.5 degrees to 2.5 degrees for visual vertical and postural vertical, and from -4.5 degrees to 4.5 degrees for haptic vertical. Of six patients with brainstem stroke and ipsilesional lateropulsion only one had an abnormal ipsilesional postural vertical tilt (6 degrees ); six had an ipsilesional visual vertical tilt (13 +/-.4 degrees ); two had ipsilesional haptic vertical tilts of 6 degrees . In 80 patients with a hemisphere stroke (35 with contralesional lateropulsion including 6 'pushers'), 34 had an abnormal contralesional postural vertical tilt (average -8.5 +/- 4.7 degrees ), 44 had contralesional visual vertical tilts (average -7 +/- 3.2 degrees ) and 26 patients had contralesional haptic vertical tilts (-7.8 +/- 2.8 degrees ); none had ipsilesional haptic vertical or postural vertical tilts. Twenty-one (26%) showed no tilt of any modality, 41 (52%) one or two abnormal modality(ies) and 18 (22%) a transmodal contralesional tilt (i.e. PV + VV + HV). Postural vertical was more tilted in right than in left hemisphere strokes and specifically biased by damage to neural circuits centred around the primary somatosensory cortex and thalamus. This shows that thalamo-parietal projections have a functional role in the processing of the somaesthetic graviceptive information. Tilts of the postural vertical were more closely related to postural disorders than tilts of the visual vertical. All patients with a transmodal tilt showed a severe lateropulsion and 17/18 a right hemisphere stroke. This indicates that the right hemisphere plays a key role in the elaboration of an internal model of verticality, and in the control of body orientation with respect to gravity. Patients with a 'pushing' behaviour showed a transmodal tilt of verticality perception and a severe postural vertical tilt. We suggest that pushing is a postural behaviour that leads patients to align their erect posture with an erroneous reference of verticality.

The peripheral nervous system and the perception of verticality.

Orientation of the body with respect to gravity is based on integration of visual, vestibular and somatosensory signals. Here, we investigated the subjective postural vertical (SPV) and visual vertical (SVV) in three patients with bilateral somatosensory deafferentation and a group of age-matched normal subjects. Our hypothesis was that the patients with bilateral somatosensory deafferentation may show tilt induced bias in the construction of their SPV, with a normal SVV. Patient 1 had a severe Guillain Barré syndrome and almost complete absence of peripheral sensation, the two other patients had a thoracic spinal injury with a sensory loss from T6-7 down. On initial testing, compared with normal subjects and the patients with spinal injury, Patient 1 had a significant bias in SPV towards the side of a preceding tilt in both directions. Several months later, after significant improvement of sensation, this tilt-induced bias in SPV had resolved completely. In addition, Patient 1 had a significantly enlarged "cone of verticality", which did not change following improvement in peripheral sensation, reflecting persisting disturbance in the perception of body verticality. In the two patients with spinal injury, bias towards the side of a preceding tilt was not significant. These findings confirm the importance of somatosensory input from the trunk to the perception of SPV in the seated position.