Francisco J. Palomar

Distinguishing SWEDDs Patients with Asymmetric Resting Tremor from Parkinson's Disease: A Clinical and Electrophysiological Study

Approximately 10% of patients diagnosed clinically with early Parkinsons disease (PD) have normal dopaminergic functional imaging (Scans Without Evidence of Dopaminergic Deficit [SWEDDs]). An important subgroup of SWEDDs are those with asymmetric rest tremor resembling parkinsonian tremor. Clinical and pathophysiological features which could help to distinguish SWEDDs from PD have not been explored. We therefore studied clinical details including non‐motor symptoms in 25 tremulous SWEDDs patients in comparison to 25 tremor‐dominant PD patients. Blinded video rating was used to compare examination findings. Electrophysiological tremor parameters and also response to a cortical plasticity protocol using paired associative stimulation (PAS) was studied in 9 patients with SWEDDs, 9 with tremor‐dominant PD (with abnormal dopamine transporter single photon emission computed tomography findings), 8 with segmental dystonia, and 8 with essential tremor (ET). Despite clinical overlap, lack of true bradykinesia, presence of dystonia, and head tremor favored a diagnosis of SWEDDs, whereas re‐emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs, and presence of non‐motor symptoms favored PD. A single tremor parameter could not differentiate between groups, but the combination of re‐emergent tremor and highest tremor amplitude at rest was characteristic of PD tremor. SWEDDs and segmental dystonia patients exhibited an abnormal exaggerated response to the PAS protocol, in contrast to a subnormal response in PD and a normal response in ET. We conclude that despite clinical overlap, there are features that can help to distinguish between PD and SWEDDs which may be useful in clinical practice. The underlying pathophysiology of SWEDDs differs from PD but has similarities with primary dystonia.

Secondary and primary dystonia: pathophysiological differences

Primary dystonia is thought to be a disorder of the basal ganglia because the symptoms resemble those of patients who have anatomical lesions in the same regions of the brain (secondary dystonia). However, these two groups of patients respond differently to therapy suggesting differences in pathophysiological mechanisms. Pathophysiological deficits in primary dystonia are well characterized and include reduced inhibition at many levels of the motor system and increased plasticity, while emerging evidence suggests additional cerebellar deficits. We compared electrophysiological features of primary and secondary dystonia, using transcranial magnetic stimulation of motor cortex and eye blink classical conditioning paradigm, to test whether dystonia symptoms share the same underlying mechanism. Eleven patients with hemidystonia caused by basal ganglia or thalamic lesions were tested over both hemispheres, corresponding to affected and non-affected side and compared with 10 patients with primary segmental dystonia with arm involvement and 10 healthy participants of similar age. We measured resting motor threshold, active motor threshold, input/output curve, short interval intracortical inhibition and cortical silent period. Plasticity was probed using an excitatory paired associative stimulation protocol. In secondary dystonia cerebellar-dependent conditioning was measured using delayed eye blink classical conditioning paradigm and results were compared with the data of patients with primary dystonia obtained previously. We found no difference in motor thresholds, input/output curves or cortical silent period between patients with secondary and primary dystonia or healthy controls. In secondary dystonia short interval intracortical inhibition was reduced on the affected side, whereas it was normal on the non-affected side. Patients with secondary dystonia had a normal response to the plasticity protocol on both the affected and non-affected side and normal eye blink classical conditioning that was not different from healthy participants. In contrast, patients with primary dystonia showed increased cortical plasticity and reduced eye blink classical conditioning. Normal motor cortex plasticity in secondary dystonia demonstrates that abnormally enhanced cortical plasticity is not required for clinical expression of dystonia, and normal eye blink conditioning suggests an absence of functional cerebellar involvement in this form of dystonia. Reduced short interval intracortical inhibition on the side of the lesion may result from abnormal basal ganglia output or may be a consequence of maintaining an abnormal dystonic posture. Dystonia appears to be a motor symptom that can reflect different pathophysiological states triggered by a variety of insults.

Effects of Two Weeks of Cerebellar Theta Burst Stimulation in Cervical Dystonia Patients

Dystonia is generally regarded as a disorder of the basal ganglia and their efferent connections to the thalamus and brainstem, but an important role of cerebellar-thalamo-cortical (CTC) circuits in the pathophysiology of dystonia has been invoked. Here in a sham controlled trial, we tested the effects of two-weeks of cerebellar continuous theta burst stimulation (cTBS) in a sample of cervical dystonia (CD) patients. Clinical evaluations were performed by administering the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). We used TMS to measure the inhibitory connectivity between the cerebellum and the contralateral motor cortex (cerebellar brain inhibition [CBI]), and the excitability of the contralateral primary motor cortex assessing intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP). Paired associative stimulation (PAS) was tested to evaluate the level and the topographical specificity of cortical plasticity, which is abnormally enhanced and non-focal in CD patients. Two weeks of cerebellar stimulation resulted in a small but significant clinical improvement as measured by the TWSTRS of approximately 15%. Cerebellar stimulation modified the CBI circuits and reduced the heterotopic PAS potentiation, leading to a normal pattern of topographic specific induced plasticity. These data provide novel evidence CTC circuits could be a potential target to partially control some dystonic symptoms in patients with cervical dystonia.

Study of cerebello-thalamocortical pathway by transcranial magnetic stimulation in Parkinson's disease.

BACKGROUND Although functional changes in the activation of the cerebellum in Parkinsons disease (PD) patients have been consistently described, it is still debated whether such altered cerebellar activation is a natural consequence of PD pathophysiology or rather it involves compensatory mechanisms. OBJECTIVE/HYPOTHESIS We used different forms of cerebellar transcranial magnetic stimulation to evaluate the hypothesis that altered cerebello-cortical interactions can be observed in PD patients and to evaluate the role of dopaminergic treatment. METHODS We studied the effects of a single cerebellar magnetic pulse over the excitability of the contralateral primary motor cortex tested with motor-evoked potentials (MEPs) (cerebellar-brain inhibition-CBI) in a group of 16 PD patients with (ON) and without dopaminergic treatment (OFF), and in 16 age-matched healthy controls. Moreover, we also tested the effects of cerebellar continuous theta-burst stimulation (cTBS) on MEP amplitude, short intracortical inhibition (SICI) and short intracortical facilitation (SICF) tested in the contralateral M1 in 13 PD patients in ON and OFF and in 16 age-matched healthy controls. RESULTS CBI was evident in controls but not in PD patients, even when tested in both ON and OFF conditions. Similarly, cerebellar cTBS reduced MEP amplitude and SICI in controls but not in PD patients under any condition. CONCLUSION(S) These results demonstrate that PD patients have deficient short-latency and long-lasting cerebellar-thalamocortical inhibitory interactions that cannot be promptly restored by standard dopaminergic medication.

The long-term outcome of orthostatic tremor

Objectives Orthostatic tremor is a rare condition characterised by high-frequency tremor that appears on standing. Although the essential clinical features of orthostatic tremor are well established, little is known about the natural progression of the disorder. We report the long-term outcome based on the largest multicentre cohort of patients with orthostatic tremor. Methods Clinical information of 68 patients with clinical and electrophysiological diagnosis of orthostatic tremor and a minimum follow-up of 5 years is presented. Results There was a clear female preponderance (76.5%) with a mean age of onset at 54 years. Median follow-up was 6 years (range 5–25). On diagnosis, 86.8% of patients presented with isolated orthostatic tremor and 13.2% had additional neurological features. At follow-up, seven patients who initially had isolated orthostatic tremor later developed further neurological signs. A total 79.4% of patients reported worsening of orthostatic tremor symptoms. These patients had significantly longer symptom duration than those without reported worsening (median 15.5 vs 10.5 years, respectively; p=0.005). There was no change in orthostatic tremor frequency over time. Structural imaging was largely unremarkable and dopaminergic neuroimaging (DaTSCAN) was normal in 18/19 cases. Pharmacological treatments were disappointing. Two patients were treated surgically and showed improvement. Conclusions Orthostatic tremor is a progressive disorder with increased disability although tremor frequency is unchanged over time. In most cases, orthostatic tremor represents an isolated syndrome. Drug treatments are unsatisfactory but surgery may hold promise.

Neurophysiological changes after intramuscular injection of botulinum toxin

Botulinum toxin (BT) acts peripherally by inhibiting acetylcholine release from the presynaptic neuromuscular terminals and by weakening muscle contraction. Therefore, its clinical benefit is primarily due to its peripheral action. As a result, local injection of BT has become a successful and safe tool in the treatment of several neurological and non-neurological disorders. Studies in animals have also shown that the toxin can be retrogradely transported and even transcytosed to neurons in the central nervous system (CNS). Further human studies have suggested that BT could alter the functional organisation of the CNS indirectly through peripheral mechanisms. BT can interfere with and modify spinal, brainstem and cortical circuits, including cortical excitability and plasticity/organisation by altering spindle afferent inflow directed to spinal motoneurons or to the various cortical areas. It is well demonstrated that the distant CNS effects of BT treatment parallel the peripheral effect, although there is limited evidence as to the cause of this. Therefore, further studies focussed on central changes after BT treatment is needed for a better understanding of these non-peripheral effects of BT.

Abnormal sensorimotor plasticity in CADASIL correlates with neuropsychological impairment

Objective Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a small vessel disease of the brain caused by mutations in the NOTCH3 gene. CADASIL progresses, in some cases, to subcortical dementia with a particular cognitive impairment. Different diseases in the dementia spectrum share a central cholinergic and sensorimotor plasticity alteration. We aimed to study different intracortical circuits and sensorimotor plasticity in CADASIL patients using transcranial magnetic stimulation protocols, and to determine whether these characteristics correlated with the results of clinical neuropsychological evaluation. Methods Ten CADASIL patients and 10 healthy subjects were included in the study. All subjects underwent a transcranial magnetic stimulation study examining different intracortical circuits. Sensorimotor plasticity was also assessed using a paired associative stimulation and extensive neuropsychological tests. Results CADASIL patients showed a lack of intracortical facilitation, short latency afferent inhibition and sensorimotor plasticity when compared with control subjects. CADASIL patients also showed an altered neuropsychological profile. Correlation between sensorimotor plasticity and neuropsychological alterations was observed in CADASIL patients. Conclusions These results suggest that acetylcholine and glutamate could be involved in the dementia process in CADASIL and that abnormal sensorimotor plasticity correlates with the neuropsychological profile in CADASIL patients.

Aberrant cortical associative plasticity associated with severe adult Tourette syndrome.

Recent studies have shown altered cortical plasticity in adult patients with Tourette syndrome. However, the clinical significance of this finding remains elusive.

Clinical features and neuropsychological profile in vascular parkinsonism

BACKGROUND The clinical profile in vascular parkinsonism (VP) patients is well described in the literature, but little is known about the neuropsychological features of this disease. The aim of our study was to evaluate the clinical characteristics and the profile of cognitive impairment in patients with VP. METHODS We prospectively evaluated 12 patients with VP, 15 with Parkinsons disease (PD) and 13 healthy controls (HC) with similar age and sex distribution. Different clinical and demographic details were collected. All subjects underwent detailed neurological and neuropsychological examinations. The neuropsychological tests included analysis of global efficiency, executive function, verbal memory, language and visuospatial function. RESULTS VP patients exhibited lower disease duration, older age at onset and higher frequency of cardiovascular risk factors. Non-motor symptoms were found to be more frequent in PD. We found that VP patients developed cognitive impairment with a significantly higher frequency than HC of a similar age. Additionally, we found that these patients had a global pattern of cognitive impairment, including executive function, verbal memory and language. Only visuospatial function was more impaired in PD than in HC. CONCLUSIONS Our data contribute to clarify the pattern of neuropsychological impairment in VP. Therefore, in the clinical evaluation, besides assessing the motor status of the patient, given that these symptoms are frequently found not to be self-reported complaints, the neurologist should evaluate them routinely as a comprehensive assessment of this disease.

Sensory perception changes induced by transcranial magnetic stimulation over the primary somatosensory cortex in Parkinson's disease

Sensory symptoms are common nonmotor manifestations of Parkinsons disease. It has been hypothesized that abnormal central processing of sensory signals occurs in Parkinsons disease and is related to dopaminergic treatment. The objective of this study was to investigate the alterations in sensory perception induced by transcranial magnetic stimulation of the primary somatosensory cortex in patients with Parkinsons disease and the modulatory effects of dopaminergic treatment. Fourteen patients with Parkinsons disease with and without dopaminergic treatment and 13 control subjects were included. Twenty milliseconds after peripheral electrical tactile stimuli in the contralateral thumb, paired‐pulse transcranial magnetic stimulation over the right primary somatosensory cortex was delivered. We evaluated the perception of peripheral electrical tactile stimuli at 2 conditioning stimulus intensities, set at 70% and 90% of the right resting motor threshold, using different interstimulus intervals. At 70% of the resting motor threshold, paired‐pulse transcranial magnetic stimulation over the right primary somatosensory cortex induced an increase in positive responses at short interstimulus intervals (1–7 ms) in controls but not in patients with dopaminergic treatment. At 90% of the resting motor threshold, controls and patients showed similar transcranial magnetic stimulation effects. Changes in peripheral electrical tactile stimuli perception after paired‐pulse transcranial magnetic stimulation over the primary somatosensory cortex are altered in patients with Parkinsons disease with dopaminergic treatment compared with controls. These findings suggest that primary somatosensory cortex excitability could be involved in changes in somatosensory integration in Parkinsons disease with dopaminergic treatment.