A multicenter double-blind randomized crossover study comparing the impact of dorsal subthalamic nucleus deep brain stimulation versus standard care on apathy in Parkinson's disease: a study protocol.

BACKGROUND: Neuroimaging studies suggest an association between apathy after deep brain stimulation (DBS) and stimulation of the ventral part of the subthalamic nucleus (STN) due to the associative fibers connected to the non-motor limbic circuits that are involved in emotion regulation and motivation. We have previously described three patients with severe apathy that could be fully treated after switching stimulation from a ventral electrode contact point to a more dorsal contact point. OBJECTIVES: To determine whether more dorsal stimulation of the STN decreases apathy compared to standard care in a multicenter randomized controlled trial with a crossover design. METHODS: We will include 26 patients with a Starkstein Apathy Scale (SAS) score of 14 or more after subthalamic nucleus (STN) deep brain stimulation (DBS) for refractory Parkinson's disease. This is a multicenter trial conducted in two teaching hospitals and one university medical center in the Netherlands after at least 3 months of STN DBS. Our intervention will consist of 1 month of unilateral dorsal STN stimulation compared to treatment as usual. The primary outcome is a change in SAS score following 1 month of DBS on the original contact compared to the SAS score following 1 month of DBS on the more dorsal contact. Secondary outcomes are symptom changes on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale motor part III, Montgomery-Åsberg Depression Rating Scale, 39-item Parkinson's disease questionnaire, Parkinson's disease impulsive-compulsive disorders questionnaire, changes in levodopa-equivalent daily dosage, apathy rated by the caregiver, and burden and quality of life of the caregiver. TRIAL REGISTRATION: ClinicalTrials.gov NL8279. Registered on January 10, 2020.

['Home away from house': an example of a reduplicative paramnesia]. / Een patiënt die dacht dat zijn huis in een ander land stond; reduplicatieve paramnesie.

We describe a 78-year old male patient with Parkinson’s disease and without a past psychiatric history, who had hallucinations and a very particular form of a delusional misidentification syndrome. His belief that he was not at home and that his home was on a different location, even in another country, is a form of 'reduplicative paramnesia'. This delusion is seen more often in association with neurodegenerative disease, for example in Parkinson’s disease. We describe the characteristics of this delusion, provide possible explanations and delineate several therapeutic options.

A comparative study of brachial plexus sonography and magnetic resonance imaging in chronic inflammatory demyelinating neuropathy and multifocal motor neuropathy.

BACKGROUND AND PURPOSE: To compare the performance of neuroimaging techniques, i.e. high-resolution ultrasound (HRUS) and magnetic resonance imaging (MRI), when applied to the brachial plexus, as part of the diagnostic work-up of chronic inflammatory demyelinating neuropathy (CIDP) and multifocal motor neuropathy (MMN). METHODS: Fifty-one incident, treatment-naive patients with CIDP (n = 23) or MMN (n = 28) underwent imaging of the brachial plexus using (i) a standardized MRI protocol to assess enlargement or T2 hyperintensity and (ii) bilateral HRUS to determine the extent of nerve (root) enlargement. RESULTS: We found enlargement of the brachial plexus in 19/51 (37%) and T2 hyperintensity in 29/51 (57%) patients with MRI and enlargement in 37/51 (73%) patients with HRUS. Abnormal results were only found in 6/51 (12%) patients with MRI and 12/51 (24%) patients with HRUS. A combination of the two imaging techniques identified 42/51 (83%) patients. We found no association between age, disease duration or Medical Research Council sum-score and sonographic nerve size, MRI enlargement or presence of T2 hyperintensity. CONCLUSIONS: Brachial plexus sonography could complement MRI in the diagnostic work-up of patients with suspected CIDP and MMN. Our results indicate that combined imaging studies may add value to the current diagnostic consensus criteria for chronic inflammatory neuropathies.

[The Othello syndrome in Parkinson's disease: an example of a lesser-known delusion]. / Het othellosyndroom bij de ziekte van Parkinson; een voorbeeld van een minder bekende waan.

Delusions are fairly common features of Parkinson's disease. Some delusions are easily recognised, but others are less well-known and can be missed by health professionals. We describe the case of a female patient with Parkinson's disease who believed, erroneously, that her partner was being unfaithful; this type of delusion is also called the Othello syndrome. After psychoeducation and the start of clozapine, the delusion faded and the relationship became more peaceful.

High resolution sonography in the evaluation of the peripheral nervous system in polyneuropathy--a review of the literature.

Clinical, laboratory and electrodiagnostic studies are the mainstay in the diagnosis of polyneuropathy. An accurate etiological diagnosis is of paramount importance to provide the appropriate treatment, prognosis and genetic counselling. High resolution sonography of the peripheral nervous system allows nerves to be readily visualized and to assess their morphology. Ultrasonography has brought pathophysiological insights and substantially added to diagnostic accuracy and treatment decisions amongst mononeuropathies. In this study the literature on its clinical application in polyneuropathy is reviewed. Several polyneuropathies have been studied by means of ultrasound: Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, multifocal motor neuropathy, paraneoplastic polyneuropathy, leprosy and diabetic neuropathy. The most prominent reported pathological changes were nerve enlargement, increased hypo-echogenicity and increased intraneural vascularization. Sonography revealed intriguingly different patterns of nerve enlargement between inflammatory neuropathies and axonal and inherited polyneuropathies. However, many studies concerned case reports or case series and showed methodological shortcomings. Further prospective studies with standardized protocols for nerve sonography and clinical and electrodiagnostic testing are needed to determine the role of nerve sonography in inherited and acquired polyneuropathies.

Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features.

OBJECTIVE: To determine the prevalence and specificity of antibodies against single gangliosides and ganglioside complexes in serum from 88 patients with multifocal motor neuropathy (MMN) and to study the association with clinical features. METHODS: ELISA was used to detect immunoglobulin (Ig)M, IgG, and IgA antibodies against GM1, GM2, GD1a, GD1b, GM1b, GT1a, GT1b, GQ1b, GalNAc-GD1a, and the glycolipid SGPG; absorption studies were performed to study cross-reactivity. Presence of antibodies against ganglioside complexes consisting of any of combinations of GM1, GM2, GD1a, GD1b, GT1b, and GQ1b was also tested. RESULTS: Anti-GM1 IgM, IgG, and IgA antibodies were detected in serum from 43%, 1%, and 5% of patients with MMN. Anti-GM2 IgM antibodies were detected in 6% and anti-GD1b IgM antibodies in 9% of patients. Patients with MMN with anti-GM1 IgM antibodies had more severe weakness (p < 0.01), more disability (p < 0.01), and more axon loss (p = 0.05) than patients without anti-GM1 IgM antibodies. Anti-GM1 IgM antibody titers correlated with Medical Research Council scores (correlation coefficient = 0.43; p < 0.0001). Anti-GD1b IgM antibody activity was associated with reduced vibration sense (p < 0.01). Absorption studies showed that anti-GD1b and anti-GM2 IgM antibodies cross-reacted with GM1. Antibodies against ganglioside complexes were not detected. Complexes containing GD1a, GD1b, GT1b, or GQ1b with GM1 lowered antibody activity against GM1. CONCLUSION: Anti-ganglioside IgM antibodies in MMN display limited specificity and are associated with severity and clinical characteristics. Results of this study suggest that anti-GM1 IgM antibodies may play a role in MMN pathogenesis.

Criteria for conduction block based on computer simulation studies of nerve conduction with human data obtained in the forearm segment of the median nerve.

The finding of conduction block (CB) on nerve conduction studies supports the diagnosis of potentially treatable immune-mediated neuropathies. CB in a number of axons may result in reduction of the compound muscle action potential (CMAP) on proximal versus distal stimulation (decrement). Decrement may also result from increased temporal dispersion (TD) as this leads to desynchronization and phase cancellation of the motor unit action potentials (MUAPs) out of which the CMAP is built up; polyphasia of MUAPs possibly yields additional decrement. To prove the occurrence of CB, decrement has to be larger than can be explained by increased TD or increased phase cancellation. This was established previously by simulations using MUAPs recorded in rats assuming maximal TD. Unfortunately, criteria based on human data and criteria for nerves with limited TD are not available. In the present study, criteria for CB were derived using simulations with thenar surface recorded MUAPs affected by collateral reinnervation that were obtained in patients with lower motor neurone disease (LMND). The effect of TD on decrement was determined for a wide range of TDs in the forearm segment of the median nerve and the segment distal to this. Our criteria for CB were based on area decrement because this was less influenced by TD and more by CB than amplitude decrement. The maximal area decrement in the forearm segment increased as TD in the forearm segment increased but decreased as TD in the distal segment increased. This suggests that, when desynchronization and phase cancellation occur in the distal segment due to TD, less phase cancellation and, therefore, less decrement can occur due to TD in the forearm. The finding that duration prolongation on proximal versus distal stimulation reflected TD within the forearm segment and that distal duration reflected TD in the distal segment allowed proposal of a more flexible set of criteria for forearm segments when TD in the forearm segment is limited or TD in the distal segment is pronounced. A separate investigation showed that the maximal TD in chronic inflammatory demyelinating polyneuropathy was within the range of our simulations, indicating that these were realistic. Our criteria were validated retrospectively in patients with multifocal motor neuropathy and patients with LMND. In the forearm segment of the median nerve, our criteria were more sensitive and equally specific for CB as compared with criteria for CB based on the study using rats. Our criteria have to be evaluated prospectively.

Axon loss is an important determinant of weakness in multifocal motor neuropathy.

BACKGROUND: Multifocal motor neuropathy (MMN) is characterised by asymmetrical weakness and muscle atrophy, in the arms more than the legs, without sensory loss. Despite a beneficial response to treatment with intravenous immunoglobulins (IVIg), weakness is slowly progressive. Histopathological studies in MMN revealed features of demyelination and axon loss. It is unknown to what extent demyelination and axon loss contribute to weakness. Unlike demyelination, axon loss has not been studied systematically in MMN. Aims/ METHODS: To assess the independent determinants of weakness in MMN, 20 patients with MMN on IVIg treatment were investigated. Using a standardised examination in each patient, muscle strength was determined in 10 muscles. In the innervating nerve of each muscle, axon loss was assessed by concentric needle electromyography, and conduction block or demyelinative slowing by motor nerve conduction studies. Multivariate analysis was used to assess independent determinants of weakness. RESULTS: Needle electromyography abnormalities compatible with axon loss were found in 61% of all muscles. Axon loss, and not conduction block or demyelinative slowing, was the most significant independent determinant of weakness in corresponding muscles. Furthermore, axon loss and conduction block were independently associated with each other. CONCLUSION: Axon loss occurs frequently in MMN and pathogenic mechanisms leading to axonal degeneration may play an important role in the outcome of the neurological deficit in patients with MMN. Therapeutic strategies aimed at prevention and reduction of axon loss, such as early initiation of treatment or additional (neuroprotective) agents, should be considered in the treatment of patients with MMN.

Ultrasonography shows extensive nerve enlargements in multifocal motor neuropathy.

Using ultrasonography we found multiple sites with nerve enlargement along the course of the brachial plexus, median, ulnar, and radial nerves in the majority of 21 patients with multifocal motor neuropathy. Sonography and electrophysiologic studies showed more abnormalities than expected on purely clinical grounds. Moreover, sonography revealed nerve enlargement without clinical or electrophysiologic abnormalities.

Criteria for demyelination based on the maximum slowing due to axonal degeneration, determined after warming in water at 37 degrees C: diagnostic yield in chronic inflammatory demyelinating polyneuropathy.

The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) is based on clinical and laboratory results and on features of demyelination found in nerve conduction studies. The criteria that are currently used to reveal demyelinative slowing in CIDP have several limitations. These criteria were only determined in lower arm and lower leg nerve segments, were not defined with respect to nerve temperature, and the relationship with distal compound muscle action potential (CMAP) amplitudes is unclear. The aim of our study was to determine criteria for demyelinative slowing for lower arm and leg segments as well as for upper arm and shoulder segments at a temperature of 37 degrees C, and to assess whether criteria have to be modified when the distal CMAP is decreased. Included were 73 patients with lower motor neuron disease (LMND), 45 patients with CIDP and 36 healthy controls. The arms and legs were warmed in water at 37 degrees C for at least 30 min prior to an investigation and thereafter kept warm with infrared heaters. The proposed criteria for demyelinative slowing were based on the maximum conduction slowing that may occur as a consequence of axonal degeneration and consisted of the upper boundary (99%) or the lower boundary (1%) of conduction values in LMND. In LMND, the maximum conduction slowing was different for arm and leg nerves and for segments within the arm nerves. Moreover, distal motor latency and motor conduction velocity were slower in nerves with distal CMAP amplitudes below 1 mV than in nerves with distal CMAP amplitudes above 1 mV. For these reasons, separate criteria were proposed for arm nerves, for leg nerves and for different segments within arm nerves, and more stringent criteria were proposed for distal motor latency and motor conduction velocity when the distal CMAP amplitude was below 1 mV. The diagnostic yield in CIDP was assessed using the nerve, and not the patient, as the unit of measurement. Thus, whether demyelinative slowing was present was determined for each nerve. Compared with other criteria, our criteria increased the specificity without affecting sensitivity. We conclude that the present criteria, based on the maximum slowing that may occur as a result of axonal degeneration, allow more accurate detection of demyelinative slowing in CIDP compared with other criteria. It should be emphasized that the proposed criteria can only be applied if the method of warming in water at 37 degrees C for at least 30 min is adopted.

Demyelination and axonal loss in multifocal motor neuropathy: distribution and relation to weakness.

Multifocal motor neuropathy (MMN) is characterized by a slowly progressive, asymmetric weakness of the limbs without sensory loss. The arms are usually affected to a greater extent than the legs, and distal muscles more than proximal muscles. The distribution of electrophysiological abnormalities and its correlation with weak muscle groups in MMN have not been investigated systematically. The aim of the present study was to assess whether electrophysiological abnormalities have a preferential or random distribution, whether electrophysiological abnormalities in a nerve correlate with weakness in the innervated muscles, and whether these results are relevant for the development of optimal electrodiagnostic protocols. We compared the pattern of weakness and electrophysiological abnormalities in 39 patients with a lower motoneuron syndrome and a positive response to intravenous immunoglobulins. All patients underwent an extensive standardized electrophysiological examination. Electrophysiological evidence of demyelination was found more often in the nerves of the arms and was distributed randomly over lower arm, upper arm and shoulder segments. Electrophysiological evidence of axonal loss presented more frequently in longer nerves, occurring most often in the leg nerves. For the arm nerves, it is possible that the length dependence of axonal loss is due to the random distribution of demyelinating lesions that lead to axonal degeneration. Weakness was associated with features of demyelination and axonal loss in the nerves of the arm, and with features of axonal loss in leg nerves. However, a substantial number (approximately one-third) of electrophysiological abnormalities were found in nerves innervating non-weakened muscles. These results imply that in MMN, conduction block is most likely to be found in long arm nerves innervating weakened muscles, but if conduction block cannot be detected in these nerves, the electrophysiological examination should be extended to other arm nerves including those innervating non-weakened muscles.

Local application of collagen containing brain-derived neurotrophic factor decreases the loss of function after spinal cord injury in the adult rat.

We studied the effect of local application of brain-derived neurotrophic factor (BDNF) on functional recovery after dorsal spinal cord transection in the adult rat. BDNF was applied at the site of the lesion in rat tail collagen type I. Locomotion was measured for 4 weeks using the BBB locomotor rating scale. One day after injury and application of BDNF the performance of treated rats was significantly increased as compared to controls (BBB-score 11.5+/-1.3 (mean +/- SEM) and 7.5+/-1.3, respectively). This difference remained significant during the first week. Histological examination of the spared spinal cord tissue at the lesion centre 4 weeks after lesioning showed no significant difference between control and BDNF-treated animals. The results indicate that local application of BDNF results in a decreased loss of function in the partially transected rat spinal cord starting one day after injury.