The Parkinson's-Reversing Breakthrough

Diets for Parkinson Disease

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"C" wave

Motoneuron disease Fasciculation atrophy Polyneuropathy Absent tendon jerks

Severe sensory deficit Alzheimer's disease Dementia

Myoclonic epilepsy Seizures Syringomyelia MSA-P

Weakness. Spasticity Sensory deficit

Rigid-akinetic syndrome

Asynchronous (1-20 Hz) Not described Not described Slow and asynchronous Not described Not described

Multifocal Slow waves Present

Epileptiform activity

Negative frontal wave

Synchronized or irregular Slow negative Present frontal wave

Asynchronous and Not described Not described irregular

Synchronous (1-12 Hz) Normal Present

Autonomic Reflexes and Functions

Autonomic nervous system dysfunction is the key to the diagnosis in patients with MSA who present with parkinsonism or cerebellar syndromes (3), and is presently a required criterion for the diagnosis of probable MSA (94). Clinically relevant autonomic dysfunctions in these patients are orthostatic hypotension, urinary and fecal incontinence, erectile dysfunction in males, sudomotor disregulation, and abnormalities in respiratory control during sleep. Autonomic dysfunction, i.e., urinary incontinence (97%) and constipation (83%), has also been reported in patients with LBD (95).

Orthostatic hypotension may result from the inability to increase sympathetic activity when standing. This can be shown as an abnormal regulation of baroreflex responses to different stimuli (96). Using readily available electrophysiological equipment, it is also possible to monitor heartbeat frequency. Recording the R-R interval variation by means of the signal trigger and the delay line unit of an electromyograph shows graphically the reduced adaptation of the heart beat rate to a postural change or to the Valsalva maneuver (77). The main drawback of this test is that patients with severe bradykinesia might be unable to perform adequately the maneuvers, and reduced R-R interval variation could actually be owing to insufficient stimulation. One of the possibilities to test R-R interval variation using methods that do not require the patient's cooperation is based on the fact that the startle response is normal in MSA patients (71,72), and on the observation that a startle accelerates heartbeat frequency in normal subjects (97). In a group of six MSA patients, a startling acoustic stimulus induced the normal motor component of the startle reaction but a significantly smaller change of the R-R interval in comparison to healthy volunteeers (98).

The sympathetic sudomotor skin response, or SSR (99), may reveal dysfunctions in the autonomic control of sudomotor reflexes. Loss of sympathetic neurons of the intermediolateral column might explain the finding of frequently abnormal SSRs in patients with MSA (100). Other tests of sudomo-tor function, such as the evaluation of the amount of sweat production to direct gland stimulation with intradermal methacholine, have also demonstrated a decreased sweat response in patients with MSA (101).

Sleep disorders are frequent in patients with MSA and in those with LBD. Some of these disorders might be related to autonomic dysfunction. In the study of Plazzi et al. (102), 35 out of 39 patients with MSA had REM sleep behavior disorders. These preceded the diagnosis in 44% of the cases. Polysomnographic studies revealed subclinical obstructive sleep apnea in 6 patients, laryngeal stridor in 8 patients, and periodic leg movements during sleep in 10 patients. Laryngeal stridor, owing to vocal cord abductor paralysis during sleep, is probably caused by selective denervation atrophy of the cricoarytenoid muscle resulting from selective loss of neurons in the nucleus ambiguous (103), and may lead to chocking and death in advanced stages of MSA. This can be prevented with tracheostomy (104) or with continuous positive air pressure (105). REM sleep behavior disorder has also been considered a sign heralding LBD (106) and, in a more recent study, it is considered as a possible hallmark of a synucleinopathy in the setting of a cognitive dementia or parkinsonism (107).

Needle EMG Recording of the Sphincter Muscles

In MSA patients, manifestations of autonomic dysfunctions such as erectile impotence are usually accompanied by increased urinary frequency and urgency, leading soon to incontinence, associated with large residual urine volumes (108). The severity of urinary symptoms is one main red flag that should warn the neurologist of the possibility that the parkinsonian patient thought to have IPD is actually facing the diagnosis of probable MSA (3). Urinary incontinence in MSA patients might be because of autonomic dysfunction, loss of pontine control of micturition, striatal sphincter denerva-tion, or a combination of them all. Striatal sphincter denervation is attributed to the selective loss of motoneurons in the nucleus of Onuff at the S2-S3 medullary segments. Needle electromyography of the external anal sphincter, therefore, is considered an important neurophysiological test in the assessment of patients with parkinsonism, as most patients with MSA show denervation-reinnerva-tion signs (109,110). We and others have confirmed that anal sphincter denervation is prominent in patients with MSA, although similar types of abnormalities have been found in a large proportion of patients with PSP as well as in some patients with IPD (111,112). Therefore, the utility of anal or vesical sphincter needle EMG in the diagnosis of MSA is still under debate (113,114). Chronic constipation, local trauma related to delivery, and other pudendal nerve long-standing lesions may give rise also to sphincter denervation (115,116), which may diminish the validity of the sign as a true marker of motoneuronal loss. In the consensus statement for the diagnosis of MSA (94), sphincter EMG abnormalities are considered as a supportive laboratory finding.

Transcranial Magnetic Stimulation

There are not many studies published on the use of transcranial magnetic stimulation (TMS) in patients with APDs in comparison to the large body of literature published in patients with IPD. However, finding an abnormality in central conduction time in a patient with parkinsonism should be considered as a red flag to warn of the likely existence of a degenerative disorder different from IPD. Central motor conduction time has been found slightly delayed in a number of patients with MSA, in both the parkinsonian (117) and cerebellar variants (118).

Many other cortical and subcortical functional measures can be determined with single-pulse TMS, including resting and active threshold, stimulus-response curves, silent period duration, or cortical maps, but only a few studies of this kind have been carried out in patients with APDs. Most of them have been performed in patients with CBD, a disorder featuring clinical signs of asymmetrical sen-sorimotor cortex involvement. Recording from muscles of the more affected side, Lu et al. (119) reported shortened TMS-induced silent period, and Strafella et al. (120) reported enhanced facilitation and reduced inhibition of MEPs modulated by digital nerve stimulation. These findings are likely reflecting motor cortical excitability enhancement.

Patients with CBD exhibit lack of voluntary control of limb movements (video segment 3), or "alien-hand" syndrome, which suggests a cortical dysfunction (121,122). In normal subjects, unilateral TMS, applied with the figure of "8" coil, induces hand muscle responses restricted to the contralateral side. However, in 6 out of 10 patients with CBD, Valls-Sole et al. (123) found bilateral responses to focal, unilateral, TMS applied to the side contralateral to the alien hand (Fig. 7). Ipsilat-eral responses were delayed with respect to the contralateral ones by a mean of 7.7 ± 2.2 ms, a time allowing for conduction through the corpus callosum. Such abnormality was not found in any of 10 normal subjects, 8 patients with Alzheimer's disease, or 6 patients with IPD presenting with predominantly unilateral rigidity. This finding points again to an enhanced motor cortex excitability in the hemisphere contralateral to the alien hand, which may be unable to inhibit transcallosal excitatory inputs from the other hemisphere.

Paired-pulse TMS has been also used in the study of corticospinal tract functions in patients with APD. Intrahemispheric cortico-cortical inhibition was found abnormally reduced in patients with MSA-P, but not in patients with MSA-C (124). It has also been abnormal in the study of patients with CBD (125,126), suggesting the possibility of its clinical utility in the early phases of the disease (126).

TMS is an important tool not only for the assessment of cortical motor function but also for the analysis of the modulatory effects that descending pathways might have on segmental reflexes. Using methods similar to those proposed by Delwaide and collaborators with auditory stimuli (81), we examined the effects of TMS on the soleus H reflex in normal subjects and in patients with parkinsonism. In healthy volunteers, TMS induced early (5-30 ms) and late (60-100 ms) phases of significant facilitation of the soleus H reflex (127). The second phase is absent or significantly reduced in about 50% of patients with IPD (82), and in all eight patients with PSP examined so far (unpublished results).

Evoked Potentials

The early components of the somatosensory evoked potentials in patients with IPD are normal, except for the N30 recorded at the frontal lobe, which shows reduced amplitude (128). According to Rossini and collaborators, the reduced amplitude of the N30 might be owing to an abnormal sensorimotor integration (129). A different kind of abnormality has been reported in patients with PSP. In these patients, Kofler and collaborators (130) reported an enhancement of the amplitude of the early components of the somatosensory evoked potentials, which was considered to be the consequence of cortical disinhibition. More recently, Miwa and Mizuno (131) confirmed the finding and proposed that the observation of enlarged somatosensory evoked potentials can be useful in the differentiation of PSP patients from other patients with movement disorders.

Fig. 7. Recordings from bilateral thenar muscles to focal, unilateral, transcranial magnetic stimulation (TMS) in a healthy control subject (A), and in a patient with CBD (B). Upper traces result from left-hemisphere TMS, and lower traces from right-hemisphere TMS. Note the presence of a delayed ipsilateral MEP in the patient.

Fig. 7. Recordings from bilateral thenar muscles to focal, unilateral, transcranial magnetic stimulation (TMS) in a healthy control subject (A), and in a patient with CBD (B). Upper traces result from left-hemisphere TMS, and lower traces from right-hemisphere TMS. Note the presence of a delayed ipsilateral MEP in the patient.

The premotor evoked potentials are abnormal in patients with IPD, likely reflecting a disturbance in preparation of the motor act. Deecke et al. (132) showed that there was a delay and reduction of the bereitschaftpotential, and abnormalities in event-related potentials have been also published. However, there are no studies of the premotor potentials in patients with APDs.

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