Cerebrospinal Fluid Norepinephrine Reductions in Man after Degeneration and Electrical Stirnulati& of the Caudate Nucleus James H. Wood, MD, Michael G. Ziegler, MD, C . Raymond Lake, MD, PhD, Ira Shoulson, MD, Benjamin R. Brooks, M D , and John M. Van Buren, M D , P h D
Lumbar cerebrospinal fluid (CSF) norepinephrine concentrations determined by radioenzymatic assay in 9 patients with caudate atrophy associated with Huntington’s disease were lower ( p < 0.02)than those i n 9 age- and sex-matched control patients. Preoperative lumbar CSF norepinephrine concentrations were determined in 5 patients undergoing stereotaxic thalamotomy. No significant alterations in prestimulation lumbar CSF norepinephrine levels were recorded 12 days after electrode installation and thalamic coagulation. Lumbar CSF norepinephrine concentrations were reduced ( p < 0.03), however, 1 2 hours following intermittent selective electrical stimulation of the caudate nucleus. These data suggest that noradrenergic pathways in man are ( 1 ) impaired in Huntington’s disease and (2) inhibited by direct caudate stimulation. Wood JH, Ziegler MG, Lake CR, et al: Cerebrospinal fluid norepinephrine reductions in man after degeneration and electrical stimulation of the caudate nucleus. A n n Neurol 1:94-99, 1977
Attempts to ameliorate the characteristic choreic symptoms of Huntington’s disease by blocking dopaminergic transmission [ 11 or compensating for choline acetylase [2, 31, serotonin [4-61, and gammaaminobutyric acid (GABA) [ 71 deficiencies have yielded limited or n o benefit. To date, the role of noradrenergic pathways in the pathophysiology of Huntington’s disease has not been determined. The first segment of our study evaluates cerebrospinal fluid (CSF) norepinephrine reductions in patients with Huntington’s disease and caudate atrophy. Neuronal degeneration within the caudate nucleus is a consistent finding in autopsy material from patients with Huntington’s disease [8], and loss of caudate function might contribute to the symptoms of this disorder. Reasoning from recent successes with cerebellar stimulation in epileptic patients with cerebellar atrophy [9- 111, extrinsic stimulation of the remaining intact caudate neurons might then compensate for the pathological reduction in caudate function secondary to atrophic changes. In accordance with such a hypothesis, caudate stimulation would be expected to result in evoked neurotransmitter alterations that
would oppose those noted in patients with caudate atrophy. Incorporating depth electrodes capable of selective stimulation at precise intervals along the shaft [ 121 and recently developed methods for accurate determination of norepinephrine levels in human CSF [13, 141, the second segment of this study evaluates the response of CSF norepinephrine concentrations to electrical stimulation of the human caudate nucleus. A preliminary abstract concerning this investigation has been published [14a].
From the Surgical Neurology, Medical Neurology, and Clinical Neurosciences Branches, National Institute of Neurological and Communicative Disorders and Stroke, and the Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
Accepted for publication July 2 7 , 1776.
94
Materials and Methods The caudate atrophy study included 9 patients with the clinical diagnosis of Huntington’s disease and a mean age of 53 * 2 (SEM) years (Table 1). Caudate atrophy was verified by computerized axial tomography (Fig 1) in 2 patients and by autopsy examination in a third patient with Huntington’s disease. For comparison, we studied 9 age- and sex-matched control patients with myasthenia gravis, peripheral neuropathies excluding clinical autonomic involvement, vascular malformations without subarachnoid hemorrhage, intrasellar nonsecreting pituitary adenoma, or mild spinal
Address reprint requests to Dr Wood, Division of Neurosurgery, The University of Pennsylvania School of Medicine, 3400 Spruce St, Philadelphia, PA 19104.
Table I . Clinical and Laborirtory Data on Patients with Huntington's Disease and Control Patient.{ Patient No., Age, and Sex
1. 40, M 2. 46, M 3. 50, M 4. 52, F 5. 53, M 6. 53, M 7. 54, M 8. 61, M 9. 64, M SEM 53 ? 2"
*
Diagnosis
CSF Norepinephrine Conccntrations (urrlml)
Huntington's disease Huntington's disease Huntington's disease Huntington's disease Huntington's disease Huntington's disease Huntington's disease Huntington's disease Huntington's disease
191 116 138 118 243 231 216 191
99
171 i 18"
Patient No., Age, and Sex 10. 38, M 11. 47, M 12. 47, M 13. 51, F 14. 51, M 15. 53, M 16. 55, M 17. 67, M 18. 67, M SEM 5 3 i- ?a
*
Diagnosis
CSF Norepinephrine Concentrations (pglml)
Pituitary adenoma Spinal cord AVM Neuropath y Occipital AVM Neuropath y Myasthenia gravis Neuropathy Spond y losis Myasthenia gravis
186 281 304 182 295 245 171 2 34 256
239 ? 17h
"No significant difference in mean age between patients with Huntington's disease and control patients. 'Significant reductions ( p < 0.02, two-tailed Student t-test) in cerebrospinal fluid norepinephrine levels i n patients with Huntington's disease compared with control patients.
AVM
=
arreriovenous malformation; SEM
=
standard error about rhe meaii
Fig I . Computerized axial tomograms, without contrust enhancement, of (A) control Putient 10 with intrasellar pituitary adenoma and iB) choreic Patient 8 with Battened caudate nucleus (arrows), cortical atrophy, and ex fi'acuo ven triular enlargement ,
Wood et al: CSF Norepinephrine and Caudate Nucleus
95
spondylosis (Table 1).The mean age of the control patients was 53 2 3 years. The caudate stimulation study [12] included 1 patient with intractable thalamic pain following evacuation of a left thalamocapsular hematoma, 1 patient with right hemiparkinsonism, 1 patient with spasmodic torticollis and retrocollis, and 2 patients with dystonia musculorum deformans (Table 2). Their mean age was 38 & 8 gears. O n admission, all patients were placed on a low monoamine diet and medications were discontinued. All oral intake and physical activity were avoided during the 18 hours preceding each lumbar puncture. Lumbar punctures were performed in the lateral decubitus position at 3 PM on both the patients with Huntington’s disease and the control patients and at 3 AM on the patients in the stimulation study. A t lumbar puncture, a 4 ml aliquot of CSF was collected in a tube containing 10 mg of ascorbic acid after 15 ml of CSF had drained from the spinal needle. This sampling technique was intended to promote CSF circulation from the ventricular outlets to the lumbar sac. After collection, CSF samples were placed on ice for less than 30 minutes before storage at -70°C [13]. The norepinephrine content of each CSF sample was determined by a radioenzymatic assay technique [13, 141 and reported in picograms per milliliter. Among the 5 patients involved in the stimulation study, lumbar CSF samples were obtained prior to thalamotomy. At operation, ventricular landmarks were established by pressure ventriculography [ 151. Using a previously described procedure [16], the coagulating tips of the depth electrodes were inserted stereotaxically i n t o the nuclei medialis centralis of the patient with thalamic pain and into the nuclei ventralis intermedius of the 4 patients with abnormal movements (Fig 2). The flexible electrode shafts, containing stimulating contacts at 5.0 mm intervals (Fig 3 ) ,
passed chrough che caudate nucleus. Detailed descriptions of these coagulating depth electrodes have been presented previously [ 121. After incremenral coagulation of the thalamic targets [17, 181, the electrode shafts were attached to the scalp using small nylon clamps [191 prior to the patient’s return to the ward. All patients received prophylactic antibiotics. Cerebrospinal fluid samples were collected 1 2 days after the installation of electrodes and coagulation of thalamic targets in order to evaluate the contribution made by the surgical procedure to CSF alterations observed after caudate stimulation. After the electrode position was verified by calibrated radiography, those contact points along the electrode shaft within the caudate nucleus were stimulated at 15-second intervals for 10 minutes using biphasic 8 to 10 mA, peak-to-peak, 2.5 msec square waves at 60 Hz frequency. The final postoperative CSF samples from these patients were obtained 12 hours following caudate stimulation to allow the ventricular fluid to diffuse to the lumbar CSF according to normal circulation patterns 1201. Thereafter, the respective thalamic targets were recoagulated prior to electrode removal. Unpaired and paired Student’s two-tailed t-tests were used to estimate the significance of results i n the caudate atrophy and caudate stimulation studies, respectively.
Results T h e m e a n CSF n o r e p i n e p h r i n e concentration of 17 1 ? 18 pg/ml i n t h e 9 patients with H u n t i n g t o n ’ s disease and caudate atrophy was lower than t h e 239 +- 17 pg/ml (p < 0.02) i n t h e 9 age- a n d sex-matched c o n t r o l patients (see T a b l e 1). The m e a n CSF n o r e p i n e p h r i n e concentration i n t h e
Table 2.Clinzral aiid Lboratorj Data o n PutzentJ i n Caudate hrflrleus S t ~ m u f a t m Stady i [I21 Patient No., Age, and Sex
19. 16, M 20. 27, M 21. 38, F
22. 45, M 23. 63, F &
Diagnosis Dystonia musculorurn deformans Dystonia musculorum deformans Thalamic pain syndrome Right hemiparkinsonism Torticollis, retrocollis
SEM 38 ? 8
CSF Norepinephrine Concentrations before Electrode Insertion (pdml)
CSF Norepinephrine Concentrations 12 Days after Electrode Insertion (t.g/ml)
CSF Norepinephrine Concentrations 12 Hours after Caudate Nucleus Stimulation (pg/ml)
371
407
257
42 7
. . .
359
553
533
410
443
356
286
48 2
612
323
455 -+ 30”
477
?
58”
327 t 27“.h
aSignificant reductions (/I < 0.01, two-tailed paired Student t-test) in cerebrospinal fluid norepinephrine levels after caudatc stimulation compared with preoperative CSF norepinephrine concentrations. ”Significant reductions (I
Lumbar cerebrospinal fluid (CSF) norepinephrine concentrations determined by radioenzymatic assay in 9 patients with caudate atrophy associated with Huntington’s disease were lower ( p < 0.02)than those i n 9 age- and sex-matched control patients. Preoperative lumbar CSF norepinephrine concentrations were determined in 5 patients undergoing stereotaxic thalamotomy. No significant alterations in prestimulation lumbar CSF norepinephrine levels were recorded 12 days after electrode installation and thalamic coagulation. Lumbar CSF norepinephrine concentrations were reduced ( p < 0.03), however, 1 2 hours following intermittent selective electrical stimulation of the caudate nucleus. These data suggest that noradrenergic pathways in man are ( 1 ) impaired in Huntington’s disease and (2) inhibited by direct caudate stimulation. Wood JH, Ziegler MG, Lake CR, et al: Cerebrospinal fluid norepinephrine reductions in man after degeneration and electrical stimulation of the caudate nucleus. A n n Neurol 1:94-99, 1977
Attempts to ameliorate the characteristic choreic symptoms of Huntington’s disease by blocking dopaminergic transmission [ 11 or compensating for choline acetylase [2, 31, serotonin [4-61, and gammaaminobutyric acid (GABA) [ 71 deficiencies have yielded limited or n o benefit. To date, the role of noradrenergic pathways in the pathophysiology of Huntington’s disease has not been determined. The first segment of our study evaluates cerebrospinal fluid (CSF) norepinephrine reductions in patients with Huntington’s disease and caudate atrophy. Neuronal degeneration within the caudate nucleus is a consistent finding in autopsy material from patients with Huntington’s disease [8], and loss of caudate function might contribute to the symptoms of this disorder. Reasoning from recent successes with cerebellar stimulation in epileptic patients with cerebellar atrophy [9- 111, extrinsic stimulation of the remaining intact caudate neurons might then compensate for the pathological reduction in caudate function secondary to atrophic changes. In accordance with such a hypothesis, caudate stimulation would be expected to result in evoked neurotransmitter alterations that
would oppose those noted in patients with caudate atrophy. Incorporating depth electrodes capable of selective stimulation at precise intervals along the shaft [ 121 and recently developed methods for accurate determination of norepinephrine levels in human CSF [13, 141, the second segment of this study evaluates the response of CSF norepinephrine concentrations to electrical stimulation of the human caudate nucleus. A preliminary abstract concerning this investigation has been published [14a].
From the Surgical Neurology, Medical Neurology, and Clinical Neurosciences Branches, National Institute of Neurological and Communicative Disorders and Stroke, and the Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
Accepted for publication July 2 7 , 1776.
94
Materials and Methods The caudate atrophy study included 9 patients with the clinical diagnosis of Huntington’s disease and a mean age of 53 * 2 (SEM) years (Table 1). Caudate atrophy was verified by computerized axial tomography (Fig 1) in 2 patients and by autopsy examination in a third patient with Huntington’s disease. For comparison, we studied 9 age- and sex-matched control patients with myasthenia gravis, peripheral neuropathies excluding clinical autonomic involvement, vascular malformations without subarachnoid hemorrhage, intrasellar nonsecreting pituitary adenoma, or mild spinal
Address reprint requests to Dr Wood, Division of Neurosurgery, The University of Pennsylvania School of Medicine, 3400 Spruce St, Philadelphia, PA 19104.
Table I . Clinical and Laborirtory Data on Patients with Huntington's Disease and Control Patient.{ Patient No., Age, and Sex
1. 40, M 2. 46, M 3. 50, M 4. 52, F 5. 53, M 6. 53, M 7. 54, M 8. 61, M 9. 64, M SEM 53 ? 2"
*
Diagnosis
CSF Norepinephrine Conccntrations (urrlml)
Huntington's disease Huntington's disease Huntington's disease Huntington's disease Huntington's disease Huntington's disease Huntington's disease Huntington's disease Huntington's disease
191 116 138 118 243 231 216 191
99
171 i 18"
Patient No., Age, and Sex 10. 38, M 11. 47, M 12. 47, M 13. 51, F 14. 51, M 15. 53, M 16. 55, M 17. 67, M 18. 67, M SEM 5 3 i- ?a
*
Diagnosis
CSF Norepinephrine Concentrations (pglml)
Pituitary adenoma Spinal cord AVM Neuropath y Occipital AVM Neuropath y Myasthenia gravis Neuropathy Spond y losis Myasthenia gravis
186 281 304 182 295 245 171 2 34 256
239 ? 17h
"No significant difference in mean age between patients with Huntington's disease and control patients. 'Significant reductions ( p < 0.02, two-tailed Student t-test) in cerebrospinal fluid norepinephrine levels i n patients with Huntington's disease compared with control patients.
AVM
=
arreriovenous malformation; SEM
=
standard error about rhe meaii
Fig I . Computerized axial tomograms, without contrust enhancement, of (A) control Putient 10 with intrasellar pituitary adenoma and iB) choreic Patient 8 with Battened caudate nucleus (arrows), cortical atrophy, and ex fi'acuo ven triular enlargement ,
Wood et al: CSF Norepinephrine and Caudate Nucleus
95
spondylosis (Table 1).The mean age of the control patients was 53 2 3 years. The caudate stimulation study [12] included 1 patient with intractable thalamic pain following evacuation of a left thalamocapsular hematoma, 1 patient with right hemiparkinsonism, 1 patient with spasmodic torticollis and retrocollis, and 2 patients with dystonia musculorum deformans (Table 2). Their mean age was 38 & 8 gears. O n admission, all patients were placed on a low monoamine diet and medications were discontinued. All oral intake and physical activity were avoided during the 18 hours preceding each lumbar puncture. Lumbar punctures were performed in the lateral decubitus position at 3 PM on both the patients with Huntington’s disease and the control patients and at 3 AM on the patients in the stimulation study. A t lumbar puncture, a 4 ml aliquot of CSF was collected in a tube containing 10 mg of ascorbic acid after 15 ml of CSF had drained from the spinal needle. This sampling technique was intended to promote CSF circulation from the ventricular outlets to the lumbar sac. After collection, CSF samples were placed on ice for less than 30 minutes before storage at -70°C [13]. The norepinephrine content of each CSF sample was determined by a radioenzymatic assay technique [13, 141 and reported in picograms per milliliter. Among the 5 patients involved in the stimulation study, lumbar CSF samples were obtained prior to thalamotomy. At operation, ventricular landmarks were established by pressure ventriculography [ 151. Using a previously described procedure [16], the coagulating tips of the depth electrodes were inserted stereotaxically i n t o the nuclei medialis centralis of the patient with thalamic pain and into the nuclei ventralis intermedius of the 4 patients with abnormal movements (Fig 2). The flexible electrode shafts, containing stimulating contacts at 5.0 mm intervals (Fig 3 ) ,
passed chrough che caudate nucleus. Detailed descriptions of these coagulating depth electrodes have been presented previously [ 121. After incremenral coagulation of the thalamic targets [17, 181, the electrode shafts were attached to the scalp using small nylon clamps [191 prior to the patient’s return to the ward. All patients received prophylactic antibiotics. Cerebrospinal fluid samples were collected 1 2 days after the installation of electrodes and coagulation of thalamic targets in order to evaluate the contribution made by the surgical procedure to CSF alterations observed after caudate stimulation. After the electrode position was verified by calibrated radiography, those contact points along the electrode shaft within the caudate nucleus were stimulated at 15-second intervals for 10 minutes using biphasic 8 to 10 mA, peak-to-peak, 2.5 msec square waves at 60 Hz frequency. The final postoperative CSF samples from these patients were obtained 12 hours following caudate stimulation to allow the ventricular fluid to diffuse to the lumbar CSF according to normal circulation patterns 1201. Thereafter, the respective thalamic targets were recoagulated prior to electrode removal. Unpaired and paired Student’s two-tailed t-tests were used to estimate the significance of results i n the caudate atrophy and caudate stimulation studies, respectively.
Results T h e m e a n CSF n o r e p i n e p h r i n e concentration of 17 1 ? 18 pg/ml i n t h e 9 patients with H u n t i n g t o n ’ s disease and caudate atrophy was lower than t h e 239 +- 17 pg/ml (p < 0.02) i n t h e 9 age- a n d sex-matched c o n t r o l patients (see T a b l e 1). The m e a n CSF n o r e p i n e p h r i n e concentration i n t h e
Table 2.Clinzral aiid Lboratorj Data o n PutzentJ i n Caudate hrflrleus S t ~ m u f a t m Stady i [I21 Patient No., Age, and Sex
19. 16, M 20. 27, M 21. 38, F
22. 45, M 23. 63, F &
Diagnosis Dystonia musculorurn deformans Dystonia musculorum deformans Thalamic pain syndrome Right hemiparkinsonism Torticollis, retrocollis
SEM 38 ? 8
CSF Norepinephrine Concentrations before Electrode Insertion (pdml)
CSF Norepinephrine Concentrations 12 Days after Electrode Insertion (t.g/ml)
CSF Norepinephrine Concentrations 12 Hours after Caudate Nucleus Stimulation (pg/ml)
371
407
257
42 7
. . .
359
553
533
410
443
356
286
48 2
612
323
455 -+ 30”
477
?
58”
327 t 27“.h
aSignificant reductions (/I < 0.01, two-tailed paired Student t-test) in cerebrospinal fluid norepinephrine levels after caudatc stimulation compared with preoperative CSF norepinephrine concentrations. ”Significant reductions (I
