Electroencephalography and clinical Neurophysiology, 85 (1992) 225-227
225
© 1992 Elsevier Scientific Publishers Ireland, Ltd. 0924-980X/92/$05.00
ELMOCO 91632 Short communication
Abnormal sympathetic skin responses in thalamic lesions P. Montagna, P. Cortelli, P. Avoni, L.P. Marchello, L. Monari, P. Tinuper, P. Gambetti and E. Lugaresi
a
Institute of Neurology, University of Bologna, Bologna (Italy), and a Institute of Pathology, Case Western Reserve University, Cleveland, OH (U.S.A.) (Accepted for publication: 4 March 1992)
Summary Sympathetic skin responses (SSRs) were abolished in 4 patients affected with fatal familial thalamic degeneration involving the anterior (A) and dorsomedial (DM) thalamic nuclei, without lesions of the peripheral vegetative system. Abnormalities of SSR were not due to peripheral nerve lesions. It is concluded that SSR integrity also depends upon thalamic formations ("visceral" thalamus) and their frontal cortical connections. Key words: Sympathetic skin response; Thalamus; Autonomic system
The sympathetic skin response (SSR) is a potential generated by variations in skin conductance induced by arousing stimuli or deep inspiration. Abnormal SSR has been reported in several types of polyneuropathy (Shahani et al. 1984; Knezevic and Bajada 1985; Soliven et al. 1985; Van den Bergh and Kelly 1986; Montagna et al. 1990) and has been shown to correlate with impaired autonomic functions (Soliven et al. 1985). Thus, SSR has been proposed as a measure of the integrity of the vegetative components of the peripheral nervous system (Shahani et al. 1984; Knezevic and Bajada 1985). Central nervous lesions could, however, also influence the presence and amplitude of the SSR. We have previously described a family clinically characterized by severe insomnia, dysautonomia and somatomotor manifestations. Post-mortem studies showed severe loss of neurones and gliosis of the anterior (A) and dorsomedial (DM) thalamic nuclei as the principal pathological markers of the disease (Lugaresi et al. 1986). More recently, we encountered another unrelated family with similar clinical and pathological findings. We report here studies on SSR performed in 4 affected patients from these 2 families.
Methods and materials SSRs were obtained in 4 patients aged 37-58 years (Table I). The clinical and autonomic symptoms and signs have been described in detail elsewhere (Lugaresi et al. 1986). Three cases belonged to the originally described family (Lugaresi et al. 1986; family A, pedigree numbers V-58, IV-16, IV-21 respectively, in Manetto et al. 1992); the fourth case belonged to the newly identified family (family B). Post-mortem examinations, done in cases V-58 and IV-21 from family A and in the single patient from family B, showed the following: in all cases, severe atrophy of the anterior (A) and dorsomedial (DM) thalamic nuclei was found with over 50% cell loss, other thalamic nuclei being less severely and inconsistently affected;
Correspondence to: Pasquale Montagna, M.D., Clinica Neurologica, Universit~ di Bologna, Via U. Foscolo 7, 40123 Bologna (Italy). Tel.: 0039/51/585158; Fax: 0039/51/6442165.
various degrees of astrogliosis, torpedo formation and atrophy were present in the cerebral cortex, cerebellum and inferior olivary nuclei, respectively; cerebral cortex spongiosis was observed only in case V-58. No abnormalities were found in the hypothalamus, basal ganglia, brain-stem or spinal cord. In cases V-58 and IV-16 from family A and in case 4 from family B, FDG-PET studies showed striking hypometabolism at the level of the thalami and some hypometabolism in the frontal cortex. Autonomic control of the cardiovascular system was assessed by means of physiological, biochemical and pharmacological tests. The details of the methods used and the data from patients 1 and 2 have already been reported (Cortelli et al. 1991). Briefly, in the resting state, blood pressure (BP), heart rate (HR) and plasma noradrenaline (NA) levels were elevated in all the patients. The results of cardiovascular reflexes are summarized in Table I. The baroreflex arc was intact (normal head-up tilt test and baroreflex sensitivity index calculated during the release phase of Valsalva manoeuvre); the sympathetic efferents were normal with an exaggerated response to certain stimuli (BP overshoot post-Valsalva manoeuvre, diastolic BP response to isometric handgrip and enhanced plasma NA levels after 10 rain of head-up tilt test); normal respiratory arrhythmia and normal HR changes during the Valsalva manoeuvre indicated the integrity of cardiac parasympathetic efferents. In summary, autonomic investigations showed imbalanced autonomic control, with preserved parasympathetic but higher sympathetic activity. SSRs were produced by means of electrical stimulation of the median nerve at the wrist and by deep inspiration, and also by recording with surface electrodes from the ipsilateral palm and sole of the foot, according to the method of Shahani et al. (1984). Electrical stimulation of the glabella, which is usually effective in eliciting SSR, was also performed (Montagna et al. 1985). Electrical stimuli, 0.2 msec in duration, were delivered randomly and infrequently in order to avoid habituation, with maximal intensities up to 100 mA if responses were absent. Limb temperature was kept constant at 36°C by means of an infrared heating lamp (500 W) fed back by a thermocouple. Normal values for SSR were from 20 normal volunteers. To exclude peripheral neuropathy, patients underwent needle EMG examinations and motor and sensory CV studies performed by means of near-nerve stimulating and recording electrodes (Buchthal and Rosenfalck 1966). Patients were drug-free
P. MONTAGNA ET AL.
226 TABLE I Summary of relevant autonomic findings. Case no.
Head-up tilt
Valsalva manoeuvre
Deep breathing
Isometric handgrip
SSR
HR
NA
A
VR
OVER
BRSI
RA
DBP
Palm normal values: (X+ S.D.)= 2.78_+ 1.5 mV
N I N II N III N
$ N N N
1` ~' 1` N
1` N N N
N N N N
$ ? 1" N
N N N N
N N N N
T $ "~ N
0 0.6 0 1
N
N
I"
N
N
$
~,
N
n.e.
0
N
1'
1'
T
N
1'
N
N
$
0
BP
Family A (1) F 37 yrs V-58 (2) F 58 yrs IV-16 (3) M 53 yrs IV-21
Family B (4) M 53 yrs
N: normal; "/': greater than controls; $: lower than controls; 0: absent; BP: blood pressure; HR: heart rate; NA: noradrenaline; A: adrenaline; VR: Valsalva ratio; OVER: overshoot; BRSI: baroreceptor sensitivity index; RA: respiratory arrhythmia; DBP" diastolic blood pressure; n.e.: not evaluated; SSR: sympathetic skin response.
at the time of examination; in case IV-16, SSRs were also obtained under phenobarbital 200 mg daily (see later), given for GM seizures.
Results EMG, motor and sensory CVs were normal. Electrical stimulation of the wrist and glabella and deep inspiration were all unsuccessful in eliciting SSRs in the palm and sole in 3 patients. In case IV-16 from family A, low-amplitude (0.6 mV in the palm, 21% of the normal mean) SSRs were obtained on first testing; SSR was absent 2 months later, associated with clinical deterioration (increased body temperature, increased salivation, lacrimation and perspiration); retesting upon introduction of phenobarbital, which ameliorated sleep and decreased perspiration, BP and NA levels, disclosed a higher amplitude (1 mV) SSR in the palm 14 months later (case IV-16, III testing).
Discussion The lack of evoked SSR in our patients was not due to the presence of lesions of the peripheral autonomic, or motor or sensory nervous fibres (polyneuropathy), since EMG, nerve CV and peripheral vegetative tests were all normal. The presence and amplitude of the SSR depend strongly upon the quality and rate of the arousing stimuli (habituation), but we were careful to deliver rare, random stimuli, and up to very high intensity. With less intense stimuli, we have never failed to obtain responses in normal controls. Thus, CNS lesions must have been responsible for the lack of SSR in our patients. As the main common (and, in case IV-21 and case 4 from family B, practically the only) pathological trait was the involvement of the thalamic nuclei, we propose that these formations are involved in the integration of the SSR. This is consistent with our hypothesis that the thalamus exerts a more general regulatory role in the balanced integration of the autonomic functions (Lugaresi et al. 1987). Follow-up studies in case IV-16 showed, moreover, that the initially low or absent SSR could recover to higher amplitude when clinical and vegetative conditions improved after treatment with phenobarbital. In our opinion this indicates that our patient lacked SSR not because of anatomic disruption of the reflex pathways, but
probably because the central "gain" modulating the response was functionally abnormal. The A and DM thalamic nuclei send projections to and receive projections from the frontal cortex, in particular the mesial-orbital regions, temporal cortex and the gyrus cinguli (Manetto et al. 1992). Abnormalities of evoked skin conductance responses to emotional stimuli have been described in patients with bilateral orbito-mesial frontal lesions (so-called "interoceptive agnosia" of Nauta) (Neafsey 1990). Our clinico-pathological report suggests that central supratentorial lesions in man may abolish SSRs. The A and DM thalamic nuclei and their cortical connections represent formations fundamental for the correct organization of sympathetic evoked activities.
References Buchthal, F. and Rosenfalck, A. Evoked action potentials and conduction velocity in human sensory nerves. Brain Res., 1966, 3: 1-122, Cortelli, P., Parchi, P., Contin, M., Pierangeli, G., Avoni, P., Tinuper, P., Montagna, P., Baruzzi, A., Gambetti, P.L. and Lugaresi, E. Cardiovascular dysautonomia in fatal familial insomnia. Clin. Auton. Res., 1991, 1: 15-21. Knezevic, W. and Bajada, S. Peripheral autonomic surface potential. A quantitative technique for recording sympathetic conduction in man. J. Neurol. Sci., 1985, 67: 239-251. Lugaresi, E., Medori, R., Montagna, P., Baruzzi, A., Cortelli, P., Lugaresi, A., Tinuper, P., Zucconi, M. and Gambetti, P.L. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. New Engl. J. Med., 1986, 315: 997-1003. Lugaresi, A., Baruzzi, A., Cacciari, E., Cortelli, P., Medori, R , Montagna, P., Tinuper, P., Zucconi, M., Roiter, I. and Lugaresi, E. Lack of vegetative and endocrine circadian rhythms in fatal familial thalamic degeneration. Clin. Endocrinol., 1987, 26: 573580. Manetto, V., Medori, R., Cortelli, P., Montagna, P., Tinuper, P., Baruzzi, A., Rancurel, G., Hauw, J.J., Vanderhaeghen, J.J., Mailleux, P., Bugiani, O., Tagliavini, F., Bouras, C., Rizzuto, N., Lugaresi, E. and Gambetti, P. Fatal familial insomnia. Clinical and pathological study of five new cases. Neurology, 1992, 42: 312-319.
SSR AND THALAMUS Montagna, P., Liguori, R. and Zappia, M. Sympathetic skin response. J. Neurol. Neurosurg. Psychiat., 1985, 48: 489-490. Montagna, P., Salvi, F., Monari, L. and Plasmati, R. Sympathetic skin response in familial amyloid polyneuropathy. In: J.B. Natvig et al. (Eds.), Amyloid and Amyloidosis. Kluwer Academic Publishers, Dordrecht, 1990: 679-682. Neafsey, E.J. Prefrontal cortical control of the autonomic nervous system: anatomical and physiological observations. In: H.B.M. Uylings, C.G. Van Eden, J.P.C. De Bruin, M.A. Corner and M.G.P. Feenstra (Eds.), Progress in Brain Research, Vol. 85. Elsevier, Amsterdam, 1990: 147-166.
227 Shahani, B.T., Halperin, J.J., Boulu, P. and Cohen, J. Sympathetic skin response: a method of assessing unmyelinated axon dysfunction in peripheral neuropathies. J. Neurol. Neurosurg. Psychiat., 1984, 47: 536-542. Soliven, B., Maselli, R., Jaspen, J., Green, A., Graziano, H. and Petersen, M. Sympathetic skin response in diabetic neuropathy. Muscle Nerve, 1985, 8: 614. Van den Bergh, P. and Kelly, J.J. The evoked electrodermal response in peripheral neuropathies. Muscle Nerve, 1986, 9: 656657.
225
© 1992 Elsevier Scientific Publishers Ireland, Ltd. 0924-980X/92/$05.00
ELMOCO 91632 Short communication
Abnormal sympathetic skin responses in thalamic lesions P. Montagna, P. Cortelli, P. Avoni, L.P. Marchello, L. Monari, P. Tinuper, P. Gambetti and E. Lugaresi
a
Institute of Neurology, University of Bologna, Bologna (Italy), and a Institute of Pathology, Case Western Reserve University, Cleveland, OH (U.S.A.) (Accepted for publication: 4 March 1992)
Summary Sympathetic skin responses (SSRs) were abolished in 4 patients affected with fatal familial thalamic degeneration involving the anterior (A) and dorsomedial (DM) thalamic nuclei, without lesions of the peripheral vegetative system. Abnormalities of SSR were not due to peripheral nerve lesions. It is concluded that SSR integrity also depends upon thalamic formations ("visceral" thalamus) and their frontal cortical connections. Key words: Sympathetic skin response; Thalamus; Autonomic system
The sympathetic skin response (SSR) is a potential generated by variations in skin conductance induced by arousing stimuli or deep inspiration. Abnormal SSR has been reported in several types of polyneuropathy (Shahani et al. 1984; Knezevic and Bajada 1985; Soliven et al. 1985; Van den Bergh and Kelly 1986; Montagna et al. 1990) and has been shown to correlate with impaired autonomic functions (Soliven et al. 1985). Thus, SSR has been proposed as a measure of the integrity of the vegetative components of the peripheral nervous system (Shahani et al. 1984; Knezevic and Bajada 1985). Central nervous lesions could, however, also influence the presence and amplitude of the SSR. We have previously described a family clinically characterized by severe insomnia, dysautonomia and somatomotor manifestations. Post-mortem studies showed severe loss of neurones and gliosis of the anterior (A) and dorsomedial (DM) thalamic nuclei as the principal pathological markers of the disease (Lugaresi et al. 1986). More recently, we encountered another unrelated family with similar clinical and pathological findings. We report here studies on SSR performed in 4 affected patients from these 2 families.
Methods and materials SSRs were obtained in 4 patients aged 37-58 years (Table I). The clinical and autonomic symptoms and signs have been described in detail elsewhere (Lugaresi et al. 1986). Three cases belonged to the originally described family (Lugaresi et al. 1986; family A, pedigree numbers V-58, IV-16, IV-21 respectively, in Manetto et al. 1992); the fourth case belonged to the newly identified family (family B). Post-mortem examinations, done in cases V-58 and IV-21 from family A and in the single patient from family B, showed the following: in all cases, severe atrophy of the anterior (A) and dorsomedial (DM) thalamic nuclei was found with over 50% cell loss, other thalamic nuclei being less severely and inconsistently affected;
Correspondence to: Pasquale Montagna, M.D., Clinica Neurologica, Universit~ di Bologna, Via U. Foscolo 7, 40123 Bologna (Italy). Tel.: 0039/51/585158; Fax: 0039/51/6442165.
various degrees of astrogliosis, torpedo formation and atrophy were present in the cerebral cortex, cerebellum and inferior olivary nuclei, respectively; cerebral cortex spongiosis was observed only in case V-58. No abnormalities were found in the hypothalamus, basal ganglia, brain-stem or spinal cord. In cases V-58 and IV-16 from family A and in case 4 from family B, FDG-PET studies showed striking hypometabolism at the level of the thalami and some hypometabolism in the frontal cortex. Autonomic control of the cardiovascular system was assessed by means of physiological, biochemical and pharmacological tests. The details of the methods used and the data from patients 1 and 2 have already been reported (Cortelli et al. 1991). Briefly, in the resting state, blood pressure (BP), heart rate (HR) and plasma noradrenaline (NA) levels were elevated in all the patients. The results of cardiovascular reflexes are summarized in Table I. The baroreflex arc was intact (normal head-up tilt test and baroreflex sensitivity index calculated during the release phase of Valsalva manoeuvre); the sympathetic efferents were normal with an exaggerated response to certain stimuli (BP overshoot post-Valsalva manoeuvre, diastolic BP response to isometric handgrip and enhanced plasma NA levels after 10 rain of head-up tilt test); normal respiratory arrhythmia and normal HR changes during the Valsalva manoeuvre indicated the integrity of cardiac parasympathetic efferents. In summary, autonomic investigations showed imbalanced autonomic control, with preserved parasympathetic but higher sympathetic activity. SSRs were produced by means of electrical stimulation of the median nerve at the wrist and by deep inspiration, and also by recording with surface electrodes from the ipsilateral palm and sole of the foot, according to the method of Shahani et al. (1984). Electrical stimulation of the glabella, which is usually effective in eliciting SSR, was also performed (Montagna et al. 1985). Electrical stimuli, 0.2 msec in duration, were delivered randomly and infrequently in order to avoid habituation, with maximal intensities up to 100 mA if responses were absent. Limb temperature was kept constant at 36°C by means of an infrared heating lamp (500 W) fed back by a thermocouple. Normal values for SSR were from 20 normal volunteers. To exclude peripheral neuropathy, patients underwent needle EMG examinations and motor and sensory CV studies performed by means of near-nerve stimulating and recording electrodes (Buchthal and Rosenfalck 1966). Patients were drug-free
P. MONTAGNA ET AL.
226 TABLE I Summary of relevant autonomic findings. Case no.
Head-up tilt
Valsalva manoeuvre
Deep breathing
Isometric handgrip
SSR
HR
NA
A
VR
OVER
BRSI
RA
DBP
Palm normal values: (X+ S.D.)= 2.78_+ 1.5 mV
N I N II N III N
$ N N N
1` ~' 1` N
1` N N N
N N N N
$ ? 1" N
N N N N
N N N N
T $ "~ N
0 0.6 0 1
N
N
I"
N
N
$
~,
N
n.e.
0
N
1'
1'
T
N
1'
N
N
$
0
BP
Family A (1) F 37 yrs V-58 (2) F 58 yrs IV-16 (3) M 53 yrs IV-21
Family B (4) M 53 yrs
N: normal; "/': greater than controls; $: lower than controls; 0: absent; BP: blood pressure; HR: heart rate; NA: noradrenaline; A: adrenaline; VR: Valsalva ratio; OVER: overshoot; BRSI: baroreceptor sensitivity index; RA: respiratory arrhythmia; DBP" diastolic blood pressure; n.e.: not evaluated; SSR: sympathetic skin response.
at the time of examination; in case IV-16, SSRs were also obtained under phenobarbital 200 mg daily (see later), given for GM seizures.
Results EMG, motor and sensory CVs were normal. Electrical stimulation of the wrist and glabella and deep inspiration were all unsuccessful in eliciting SSRs in the palm and sole in 3 patients. In case IV-16 from family A, low-amplitude (0.6 mV in the palm, 21% of the normal mean) SSRs were obtained on first testing; SSR was absent 2 months later, associated with clinical deterioration (increased body temperature, increased salivation, lacrimation and perspiration); retesting upon introduction of phenobarbital, which ameliorated sleep and decreased perspiration, BP and NA levels, disclosed a higher amplitude (1 mV) SSR in the palm 14 months later (case IV-16, III testing).
Discussion The lack of evoked SSR in our patients was not due to the presence of lesions of the peripheral autonomic, or motor or sensory nervous fibres (polyneuropathy), since EMG, nerve CV and peripheral vegetative tests were all normal. The presence and amplitude of the SSR depend strongly upon the quality and rate of the arousing stimuli (habituation), but we were careful to deliver rare, random stimuli, and up to very high intensity. With less intense stimuli, we have never failed to obtain responses in normal controls. Thus, CNS lesions must have been responsible for the lack of SSR in our patients. As the main common (and, in case IV-21 and case 4 from family B, practically the only) pathological trait was the involvement of the thalamic nuclei, we propose that these formations are involved in the integration of the SSR. This is consistent with our hypothesis that the thalamus exerts a more general regulatory role in the balanced integration of the autonomic functions (Lugaresi et al. 1987). Follow-up studies in case IV-16 showed, moreover, that the initially low or absent SSR could recover to higher amplitude when clinical and vegetative conditions improved after treatment with phenobarbital. In our opinion this indicates that our patient lacked SSR not because of anatomic disruption of the reflex pathways, but
probably because the central "gain" modulating the response was functionally abnormal. The A and DM thalamic nuclei send projections to and receive projections from the frontal cortex, in particular the mesial-orbital regions, temporal cortex and the gyrus cinguli (Manetto et al. 1992). Abnormalities of evoked skin conductance responses to emotional stimuli have been described in patients with bilateral orbito-mesial frontal lesions (so-called "interoceptive agnosia" of Nauta) (Neafsey 1990). Our clinico-pathological report suggests that central supratentorial lesions in man may abolish SSRs. The A and DM thalamic nuclei and their cortical connections represent formations fundamental for the correct organization of sympathetic evoked activities.
References Buchthal, F. and Rosenfalck, A. Evoked action potentials and conduction velocity in human sensory nerves. Brain Res., 1966, 3: 1-122, Cortelli, P., Parchi, P., Contin, M., Pierangeli, G., Avoni, P., Tinuper, P., Montagna, P., Baruzzi, A., Gambetti, P.L. and Lugaresi, E. Cardiovascular dysautonomia in fatal familial insomnia. Clin. Auton. Res., 1991, 1: 15-21. Knezevic, W. and Bajada, S. Peripheral autonomic surface potential. A quantitative technique for recording sympathetic conduction in man. J. Neurol. Sci., 1985, 67: 239-251. Lugaresi, E., Medori, R., Montagna, P., Baruzzi, A., Cortelli, P., Lugaresi, A., Tinuper, P., Zucconi, M. and Gambetti, P.L. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. New Engl. J. Med., 1986, 315: 997-1003. Lugaresi, A., Baruzzi, A., Cacciari, E., Cortelli, P., Medori, R , Montagna, P., Tinuper, P., Zucconi, M., Roiter, I. and Lugaresi, E. Lack of vegetative and endocrine circadian rhythms in fatal familial thalamic degeneration. Clin. Endocrinol., 1987, 26: 573580. Manetto, V., Medori, R., Cortelli, P., Montagna, P., Tinuper, P., Baruzzi, A., Rancurel, G., Hauw, J.J., Vanderhaeghen, J.J., Mailleux, P., Bugiani, O., Tagliavini, F., Bouras, C., Rizzuto, N., Lugaresi, E. and Gambetti, P. Fatal familial insomnia. Clinical and pathological study of five new cases. Neurology, 1992, 42: 312-319.
SSR AND THALAMUS Montagna, P., Liguori, R. and Zappia, M. Sympathetic skin response. J. Neurol. Neurosurg. Psychiat., 1985, 48: 489-490. Montagna, P., Salvi, F., Monari, L. and Plasmati, R. Sympathetic skin response in familial amyloid polyneuropathy. In: J.B. Natvig et al. (Eds.), Amyloid and Amyloidosis. Kluwer Academic Publishers, Dordrecht, 1990: 679-682. Neafsey, E.J. Prefrontal cortical control of the autonomic nervous system: anatomical and physiological observations. In: H.B.M. Uylings, C.G. Van Eden, J.P.C. De Bruin, M.A. Corner and M.G.P. Feenstra (Eds.), Progress in Brain Research, Vol. 85. Elsevier, Amsterdam, 1990: 147-166.
227 Shahani, B.T., Halperin, J.J., Boulu, P. and Cohen, J. Sympathetic skin response: a method of assessing unmyelinated axon dysfunction in peripheral neuropathies. J. Neurol. Neurosurg. Psychiat., 1984, 47: 536-542. Soliven, B., Maselli, R., Jaspen, J., Green, A., Graziano, H. and Petersen, M. Sympathetic skin response in diabetic neuropathy. Muscle Nerve, 1985, 8: 614. Van den Bergh, P. and Kelly, J.J. The evoked electrodermal response in peripheral neuropathies. Muscle Nerve, 1986, 9: 656657.
