Movement Disorders Vol. 18, No. 1, 2003, pp. 60 – 69 © 2002 Movement Disorder Society Secondary Cervical Dystonia Associated with Structural Lesions of the Central Nervous System Mark S. LeDoux, MD, PhD,* and Kimberly A. Brady, DO University of Tennessee Health Science Center, Department of Neurology, Memphis, Tennessee, USA Abstract: We tested the hypothesis that structural lesions of the central nervous system (CNS) associated with cervical dystonia more commonly involve the cerebellum and its primary afferent pathways than basal ganglia structures. Cervical dystonia is the most common focal dystonia, the majority of cases are idiopathic, and only a small percentage of patients have a family history of dystonia or other movement disorders. Pathophysiological mechanisms operative in solely or predominantly appendicular dystonias such as writer’s cramp and Oppenheim’s dystonia, respectively, may not be directly applicable to axial dystonias. The localization of structural lesions of the CNS associated with secondary cervical dystonia may provide some insight into the neural structures potentially involved in primary cervical dystonia. The National Library of Medicine Gateway (from 1960) and a clinical database maintained by the senior author (from 1999) were searched for cases of secondary cervical dystonia associated with structural lesions of the CNS. Search terms included one or more of the following: dystonia, torticollis, cervical, secondary, and symptomatic. Lesion localization and type, patient age, patient gender, head position, occurrence of sensory tricks, and associated neurological findings were tabulated for each case. Structural lesions associated with cervical dystonia were most commonly localized to the brainstem and cerebellum. The remaining cases were equally divided between the cervical spinal cord and basal ganglia. Although inconsistent, head rotation tended to be contralateral to lesion localization. Additional neurological abnormalities were present in the majority of patients with secondary cervical dystonia. The relative paucity of basal ganglia pathology and concentration of lesions in the brainstem, cerebellum, and cervical spinal cord in patients with secondary cervical dystonia suggests that dysfunction of cerebellar afferent pathways may be important to the pathophysiology of primary cervical dystonia. © 2002 Movement Disorder Society Key words: dystonia; olivocerebellar; cervical; torticollis; stroke Cervical dystonia is the most common of the focal dystonias.1,2 It is characterized by sustained, involuntary, active contractions of cervical muscles resulting in abnormal head movements or postures.3 The vast majority of cases are idiopathic. Secondary cervical dystonia is uncommon, even in movement disorders clinics. Secondary dystonia, in general, has been associated with a wide variety of vascular, traumatic, infectious, and toxic processes affecting the central or peripheral nervous systems.4 Secondary dystonia is also a common accompaniment of heredodegenerative diseases such as Wilson’s disease, progressive supranuclear palsy, and corticalbasal ganglionic degeneration. The network abnormalities associated with both primary and secondary dystonias are poorly understood. Functional imaging,5–7 intraoperative recordings,8,9 physiological studies in humans with focal and generalized primary dystonia, animal models of both focal and generalized dystonia,10,11 and immunohistochemical localization of torsinA in human brain12 have failed to generate a cohesive pathophysiological model of dystonia. Work to date suggests, instead, that dystonia may be caused by a variety of local network abnormalities with similar effects on motor output. Along these lines, cases of secondary dystonia associated with discrete structural lesions of the central nervous system (CNS) may be important for understanding the pathophysiology of the different focal dystonias. Clinical–pathological correlation of this type has been critical for understanding the oculomotor and vestibular systems. *Correspondence to: Mark S. LeDoux, University of Tennessee Health Science Center, Department of Neurology, 855 Monroe Avenue, Link Building-Suite 415, Memphis, TN 38163. E-mail: mledoux@utmem.edu Received 31 October 2001; Revised 27 February 2002; Accepted 21 June 2002 60 SECONDARY CERVICAL DYSTONIA Hemidystonia, hand dystonia, and blepharospasm are most commonly associated with lesions of the corpus striatum, thalamus, and rostral brainstem/mesencephalon, respectively.13–15 The importance of the cerebellum, particularly the vermis and fastigial nucleus, in the control of head position suggests that the cerebellum may play a role in cervical dystonia.16 –18 The vermis and fastigial nucleus receive projections from climbing fibers that originate in the inferior olive and either direct (fastigial nucleus) or indirect (vermis) projections from a wide-variety of pre-cerebellar cell groups. Cases of secondary cervical dystonia associated with discrete structural lesions of the CNS were collected and characterized to test the hypothesis that structural lesions of the CNS associated with cervical dystonia are concentrated in olivocerebellar and pre-olivary structures. MATERIALS AND METHODS The National Library of Medicine Gateway (from 1960) and a clinical database of over 1200 patients evaluated by M.S.L. from 1999 to 2001 were searched for cases of secondary cervical dystonia associated with structural lesions of the CNS. Search terms included one or more of the following: dystonia, torticollis, cervical, secondary, and symptomatic. Lesion localization, lesion type, patient age, patient gender, head position, occurrence of sensory tricks (i.e., geste antagoniste), and associated neurological findings were tabulated for each case. Care was taken to exclude nondystonic causes of abnormal head postures such as bony and congenital abnormalities of the cervical spine or skull base, congenital muscular torticollis, retropharyngeal and paraspinal infections, and reflex cervical spasm secondary to meningeal irritation.4,19,20 Cases of cervical dystonia associated with isolated compression of the cranial nerves or cervical roots by mass lesions or vascular structures were also excluded from the analysis. Patients with cervical dystonia as part of generalized, cranio-cervical, or multifocal dystonia were not included in the analysis. RESULTS The senior author’s database contained 28 new cases of cervical dystonia over a 3-year period. Fourteen of these were cases of secondary cervical dystonia or cervical dystonia associated with heredodegenerative diseases.4 Four of the secondary cervical dystonia cases were associated with structural lesions of CNS. Case 1 A 55-year-old man developed the acute onset of left hemiparesis and dysarthria. On initial neurological examination, the patient was noted to have bilateral abdu- 61 cens paresis, left facial paresis, left hemiparesis, and left hemihypesthesia. He was diffusely hyperreflexic and had bilateral Babinski responses. Computed tomography (CT) scan of the brain demonstrated a 15 mm hemorrhage centered in the right pons with some extension across the midline (Fig. 1, Case 1). Within 12 hours of admission, the patient began complaining of neck pain. One day after admission, the patient continued to complain of neck pain and was noted to have developed cervical dystonia with rotation of his head to the left and abnormal contraction of the right sternocleidomastoid muscle. Initially, the patient was unable to actively move his head to the right. Over the subsequent 4 to 6 weeks, however, he was increasingly able to move his head toward but not across the midline. There was no significant retrocollis/anterocollis, lateral shift, sagittal shift, or shoulder elevation. Cervical dystonia persisted and the patient developed progressive hypertrophy of the right sternocleidomastoid muscle. The patient died shortly after transfer to a nursing home. Case 2 A 42-year-old woman presented for neurological evaluation after experiencing two brief episodes of ataxia and tinnitus 3 to 4 months earlier. Each episode lasted for approximately 20 minutes and was followed by a migraine headache. There was no interictal ataxia. The patient had a long history of infrequent migraine headaches and the paroxysms that she described were believed to be complicated migraine headaches. Neurological examination showed mild head rotation to the left and right laterocollis with subtle hypertrophy of the right sternocleidomastoid muscle. There was mild right shoulder elevation but no significant anterocollis/retrocollis, lateral shift, or sagittal shift. There were no other neurological abnormalities. There was no family history of movement disorders. The patient had never been treated with neuroleptics or anti-emetics. Audiometry was normal. A magnetic resonance image (MRI) of the brain demonstrated a small cystic lesion in the left cerebellopontine angle just posterior to the left facial/vestibulocochlear nerve complex with mild distortion of the rostral medulla (Fig. 1, Case 2). The MR lesion was interpreted to be an arachnoid cyst by a neuroradiologist. The patient refused both oral medications and botulinum toxin for treatment of her dystonia. Case 3 A 67-year-old, right-handed woman fractured her sternum and multiple ribs after falling down her stairs at home. There was no cervical fracture or instability. She developed abnormal head posturing several days after Movement Disorders, Vol. 18, No. 1, 2003 62 M.S. LEDOUX AND K.A. BRADY FIG. 1. Case 1: Non-contrasted CT images show a 15-mm hemorrhage centered in the right pontine tegmentum. Case 2: T2-weighted magnetic resonance images (MRI) through the posterior fossa show a 2-cm arachnoid cyst (large arrow) in the left cerebellopontine angle immediately caudal to the left facial/vestibulocochlear nerve complex with mild distortion of the rostral medulla (smaller arrow). Case 3: Magnetic resonance fluid-attenuated inversion-recovery (FLAIR) sequences show multiple high-signal abnormalities in the pontine tegmentum. Case 4-A: T2-weighted MRI shows bilateral ischemic infarctions localized to the pontine tegmentum. Case 4-B: T2-weighted MRI shows an ischemic infarction of the left thalamus. Case 4-C: T2-weighted MRI demonstrates a posterior cerebral artery distribution ischemic infarction involving the left occipital lobe. admission. MRI of the brain obtained during hospitalization showed signal abnormalities in the pons and caudal midbrain consistent with multifocal ischemic lesions (Fig. 1, Case 3). On magnetic resonance angiography of the head and neck vessels, there were no focal areas of stenosis and no evidence for vertebral artery dissection. On outpatient neurological examination approximately Movement Disorders, Vol. 18, No. 1, 2003 one year later, the patient was noted to have a right conjugate horizontal gaze deficit. She had cervical dystonia with severe right laterocollis and anterocollis along with moderate elevation and anterior displacement of the right shoulder. Her head was mildly rotated to the left. When the patient was awake, her head posture was almost fixed and could not be significantly altered either SECONDARY CERVICAL DYSTONIA actively or passively. The patient’s head posture did normalize, according to her husband, when she was asleep. The patient was mildly dysarthric. She had a very mild right hemiparesis. The patient had increased tone in the right upper extremity with cogwheeling at the wrist. There was a parkinsonian-type resting tremor of the distal right upper extremity. There was also a mild action tremor in the right upper extremity with both postural and kinetic components. There was no significant appendicular ataxia. Reflexes were brisk bilaterally in both the arms and legs. Plantar reflexes were equivocal bilaterally. The patient was ambulatory with a four-legged walker. Her gait was both spastic and ataxic. She had marked postural instability. The patient’s parkinsonism was treated with carbidopa–levodopa (25/100). At a dosage of one carbidopa– levodopa (25/100) p.o. three times daily, both her tremor and right upper extremity hypertonicity resolved. In addition, there was modest improvement in her postural instability. Her cervical dystonia did not improve with carbidopa–levodopa. With electromyographically guided botulinum toxin injections there was moderate improvement in her neck posture and pain. Case 4 A 72-year-old man with a history of hypertension and gout presented to the emergency room with a 2-day history of altered mental status. On initial neurological examination, the patient was awake and alert but disoriented in all spheres. He had moderately severe anomia, right homonymous hemianopsia, mild perseveration, and right hemihypesthesia. As shown in Figure 1 (Case 4A– C), MRI of the brain demonstrated subacute infarctions of the pons, left posterior thalamus, and left occipital lobe. One day after presentation, the patient was noted to have developed cervical dystonia with moderately severe head rotation to the left. There was mild retrocollis. There was no significant laterocollis, lateral shift, sagittal shift, or shoulder elevation. Over the course of the patient’s month-long hospital stay, his cervical dystonia slowly improved but was still present at the time of discharge to a nursing home. He died, apparently from sepsis, before his return clinic visit. RESULTS As shown in Table 1, critical clinical features (lesion localization, lesion type, patient age, patient gender, occurrence of sensory tricks, head position, and associated neurological findings) were tabulated for a total of 25 cases of secondary cervical dystonia. Four of the cases were from the senior author’s database and 21 were published previously. Thirteen of the 25 patients were 63 female (52%). Age at presentation ranged from 9 months to 72 years with a mean of 38 years. The largest percentage of cases of secondary cervical dystonia was associated with structural lesions of the brainstem (medulla, pons) and/or cerebellum (n ⫽ 11, 44%).21–24 Of these 11 lesions, three were isolated to the pons and two were isolated to the cerebellum. The tegmentum was involved by all of the pontine lesions. There were single midbrain25 and frontal lobe26 lesions. The remaining lesions were equally divided between the cervical spinal cord (n ⫽ 6, 24%)27–30 and basal ganglia (n ⫽ 6, 24%).14,31–34 All but one of the spinal cord lesions had bilateral components. Three of the basal ganglia lesions were isolated to the putamen.31,32 The other three basal ganglia lesions involved the head of the caudate nucleus and adjacent white matter.14,33,34 In the majority of cases, cervical dystonia included significant components of laterocollis, anterocollis–retrocollis, or shoulder elevation in addition to head rotation. The clinical information was inadequate to completely characterize head posture in several reports. In cases with both head rotation and a unilateral structural lesion (n ⫽ 13), the direction of head rotation was contralateral to lesion localization in 9 cases and ipsilateral in 4 cases. Head rotation was contralateral to basal ganglia and cerebral lesions in all but one case. With cerebellar, brainstem (medulla, pons), and spinal cord lesions, head rotation was ipsilateral to lesion localization in 3 cases and contralateral in 4 cases. Additional neurological abnormalities were present in 18 of the 25 cases of secondary cervical dystonia. Of the 7 cases with isolated cervical dystonia, 3 were associated with lesions of the putamen, 2 with posterior fossa masses, and 2 with tumors of the basal ganglia and adjacent white matter. Sensory tricks were reported in 5 of the 25 cases. The presence or absence of sensory tricks was not reported in 15 of the 25 cases. None of the patients with sensory tricks had basal ganglia lesions. The temporal relationship between the onset of cervical dystonia and associated structural lesions was impossible to determine in the majority of the cases. Clearly, this relationship could not be determined in patients with tumors such as gliomas and schwannomas or other mass lesions like arachnoid cysts. In cases of cervical dystonia associated with strokes, however, onset was usually within a few days of the ictus. Clinical follow-up was available for 17 of the 25 cases. Nine of these patients had significant improvement or resolution of their cervical dystonia with surgery (n ⫽ 4), botulinum toxin injections (n ⫽ 4), or a combination of the two (n ⫽ 1). Three patients showed some benefit from oral medications. Movement Disorders, Vol. 18, No. 1, 2003 LeDoux and Brady LeDoux and Brady LeDoux and Brady LeDoux and Brady Boisen 1979 Boisen 1979 Kiwak et al. 1983 Kiwak et al. 1983 Kiwak et al. 1983 Marsden et al. 1985 Isaac and Cohen 1989 Plant et al. 1989 Tranchant et al. 1991 Klostermann et al. 1993 2 3 4 5 6 7 8 9 10 11 12 13 14 Reference 1 Case no. Movement Disorders, Vol. 18, No. 1, 2003 34/F 53/F 30/F 28/M 38/M 0.75/F 3/M 10/M 32/F 39/M 72/M 67/F 42/F 55/M Age (yr)/ gender Multiple sclerosis plaque Cavernous angioma Multiple sclerosis plaques Hemorrhage Calcified angioma Low-grade glioma Intramedullary glioma with syrinx Grade II astrocytoma with syrinx Ependymoma Hemangioblastoma Ischemic infarctions Ischemic infarctions Arachnoid cyst Hemorrhage Lesion type Posterolateral R C2 R cerebellar hemisphere R midbrain, R cerebellar hemisphere R putamen Cervical and thoracic cord R caudate nucleus and adjacent white matter Midline between cerebellar tonsils and medulla Cervical cord to conus medullaris Medulla to conus medullaris Bilateral pontine tegmentum, L thalamus, L occipital lobe L cerebellar hemisphere Bilateral pontine tegmentum L cerebello-pontine angle R pons Lesion localization Rotation L, anterocollis, laterocollis Rotation-L Rotation-L, R shoulder elevation Rotation-L Rotation-L, R laterocollis Anterocollis, R laterocollis Rotation-R, L laterocollis Rotation L L laterocollis, anterocollis Rotation-R Rotation-L Rotation-L, R laterocollis R laterocollis, anterocollis Rotation-L Head position Yes NA Yes NA NA NA NA NA NA NA No No No No Sensory trick TABLE 1. Twenty-five cases of secondary cervical dystonia Urinary incontinence, hyperreflexia, optic atrophy L, mild ataxia Gait ataxia, optic atrophy, spastic paraparesis R hemihypotonia None Shoulder girdle muscle wasting, hyperreflexia None Urinary incontinence Paraparesis None Nystagmus Dysarthria, hyperreflexia, impaired conjugate gaze to R R homonymous hemianopsia, anomia, R hemi-hypesthesia Bilateral abducens palsy, left hemiparesis None Other neurological abnormalities Follow-up Marked improvement with botulinum toxin Persisted for 1 yr and then improved over weeks NA Temporary improvement after resection Some benefit from trihexyphenidyl NA NA NA NA NA Moderate improvement without treatment Moderate improvement with botulinum toxin NA Mild improvement without treatment 64 M.S. LEDOUX AND K.A. BRADY Schwartz et al. 1995 Caress et al. 1996 Soland et al. 1996 Krause et al. 1997 Krause et al. 1997 19 20 21 22 23 48/F 52/F 13/F 42/M 47/F 4/M 63/M 40/M 23/M 41/F 68/F Age (yr)/ gender Lesion type Syrinx Meningioma Schwannoma adherent to CN IX, CN X Schwannoma adherent to CN IX, CN X, & CN XI Angioblastic meningioma Gangliocytoma Ischemic infarction Mixed grade III glioma Ependymoma Ischemic infarction Ischemic infarction Roman numerals refer to respective cranial nerves. C, cervical; CN, cranial nerve; NA, not available. Hill et al. 1999 Schulz-Bunhage and Ferbert 1995 18 25 Cammerota et al. 1995 17 Krause et al. 1997 Molho and Factor 1993 16 24 Molho and Factor 1993 Reference 15 Case no. C2 to thoracic cord L cerebello-pontine angle with compression of cervical cord, brainstem, and cerebellum L cerebello-pontine angle with compression of brainstem R cerebello-pontine angle with compression of brainstem R cerebellum, medulla, pons, cervical spinal cord R frontal R basal ganglia and frontoparietal white matter R caudate putamen, and anterior limb internal capsule C2 to C5 L putamen L putamen Lesion localization Rotation-L, L laterocollis, anterocollis, L shoulder elevation, head tremor Rotation-L, L laterocollis, retrocollis Rotation-R Rotation-L, L laterocollis, L shoulder elevation Rotation-L Rotation-R, L laterocollis, R shoulder elevation Rotation-L R laterocollis Rotation-R, mild L laterocollis &L shoulder elevation Rotation-R, R laterocollis, mild anterocollis Rotation-R, L laterocollis Head position TABLE 1. (Continued) NA Yes NA NA Yes NA NA NA Yes NA NA Sensory trick Postural instability, reduced vibratory and proprioception sensation in feet R facial paresis with synkinesis L hypacusis, ataxia, dysarthria, nystagmus Head tremor, poor short-term memory, reduced attention L hypacusis Gait ataxia, hyperreflexia Hyperreflexia None Gait ataxia, paraparesis None None Other neurological abnormalities Mild improvement with botulinum toxin and medications Some improvement with botulinum toxin and medications Mild improvement with surgery, marked improvement with botulinum toxin Resolution at an interval after surgery Improvement after subtotal resection of tumor Improvement after resection of tumor Resolution with surgical removal of tumor Dystonia resolved after tumor extended into the internal capsule None Successfully treated with botulinum toxin Successfully treated with botulinum toxin Follow-up SECONDARY CERVICAL DYSTONIA 65 Movement Disorders, Vol. 18, No. 1, 2003 66 M.S. LEDOUX AND K.A. BRADY DISCUSSION Four new cases of secondary cervical dystonia associated with structural lesions of the CNS have been described and cases reported previously have been reviewed to determine those neural networks potentially involved in cervical dystonia. The cases that we have presented underscore the difficulties in establishing causal relationships between CNS lesions and focal dystonias and highlight the complex and, possibly, heterogeneous pathophysiology of cervical dystonia. Three of the 4 cases either had multiple lesions or more than one potential etiological mechanism. For example, in Case 4 the initial MRI demonstrated lesions of the pons, thalamus, and occipital lobe. In this case, was cervical dystonia caused by the pontine lesions or by the combination of pontine, thalamic, and occipital lesions? Because head rotation was ipsilateral to the thalamic lesion, it may be that the pontine lesions were causally related to the patient’s cervical dystonia. The clinical similarities between secondary and primary cervical dystonia suggests that pinpointing the networks involved in the former may be applicable to the latter. Like patients with primary cervical dystonia, the majority of patients with secondary cervical dystonia exhibited head postures that were not limited to pure rotation. Patients with secondary cervical dystonia responded to treatments such as botulinum toxin injections and anticholinergics that are used for patients with primary cervical dystonia. Sensory tricks (i.e., geste antagoniste) have been reported in several patients with secondary cervical dystonia. Finally, some patients with secondary cervical dystonia associated with structural lesions of the CNS had no other abnormalities on neurological examination. Secondary cervical dystonia must be distinguished from nondystonic causes of torticollis and other abnormal head postures.4.19,20 Some authors have used the term “pseudodystonia” to classify disorders that are associated with sustained muscle contractions as a reflex mechanism or reaction to some other problem such as Sandifer syndrome or trochlear nerve palsy.4 Pseudodystonia and nondystonia causes of torticollis would include abnormal head posturing as an attempt to reduce painful meningeal irritation, nausea, or vomiting associated with cervical and posterior fossa mass lesions or infections. Psychiatric, orthopedic, and congenital disorders simulating dystonia must be excluded by historical information, physical examination, and appropriate imaging studies.20 Review of Table 1 supports our hypothesis that structural lesions of the CNS associated with cervical dysto- Movement Disorders, Vol. 18, No. 1, 2003 nia are concentrated in regions immediately afferent to the cerebellum including the pons, medulla, and spinal cord. A much smaller percentage of lesions were localized to the “basal ganglia.” In addition, half of these “basal ganglia” lesions appeared to involve the anterior limb of the internal capsule, which contains fronto-pontine and other descending fiber systems. One feature common to most of the lesions listed in Table 1 is disruption of excitatory projections to the inferior olive or cerebellum. Olivocerebellar dysfunction plays an important role in at least three rodent models of dystonia. First, a defect in transmission of information from the inferior olive to Purkinje cells in cerebellar cortex is central to the pathophysiology of dystonia exhibited by the genetically dystonic (dt) rat.11,35–38 Second, rats treated with a neurotoxin (3-acetylpyridine) that selectively destroys inferior olivary neurons develop a movement disorder very similar to the dt rat’s generalized dystonia.39 Third, the mutant mouse tottering (tg) exhibits paroxysmal dystonia that is abolished on the Purkinje cell degeneration (pcd) mutant background.40 One obvious conclusion based on a review of behavioral and electrophysiological studies in these rodent models is that a defect in climbing fiber excitation of Purkinje cells in cerebellar cortex can produce dystonia. Because climbing fibers originate in the inferior olive, higher-order defects in excitatory neurotransmission (i.e., olivary afferents) may also produce dystonia. The inferior olive receives a wide variety of excitatory and GABAergic projections. Inferior olivary afferents arise from multiple areas including the spinal cord, medulla, pons, midbrain, cerebellar nuclei, and frontal cortex.41– 44 Projections from the red nucleus, periaqueductal gray, and other midbrain nuclei such as the interstitial nucleus of Cajal and nucleus of Darkschewitsch enter the central tegmental tract, descend uncrossed, and terminate in the inferior olive.45– 47 Fibers ascending in the spinal cord reach the inferior olive either directly through the spino-olivary tract that courses through the anterior funiculus or indirectly via the dorsal column nuclei.42,43 The specific idea that secondary cervical dystonia may be caused by a defect in inferior olivary afferents receives some indirect support from lesion and pharmacological studies in animals. For example, cervical dystonia has been produced in monkeys by creating electrolytic midbrain lesions48 –50 and, in rats, by injecting sigma receptor agonists into the red nucleus.51 This evidence is, of course, nonspecific because both the red nucleus and midbrain nuclei send projections to several caudal structures besides the inferior olive. SECONDARY CERVICAL DYSTONIA In addition to the localization data presented in Table 1, the general idea that idiopathic cervical dystonia may not be due to a primary “basal ganglia” abnormality is suggested by a wide variety of physiological studies in humans. Acoustic reflex,52 blink reflex, and masseter inhibitory reflex abnormalities in patients with cervical dystonia indicate the presence of abnormally excitable brainstem interneuronal pathways.53 Impaired vestibulocollic54 and vestibulo-ocular55 reflexes in patients with cervical dystonia and the appearance of cervical dystonia after unilateral vestibular nerve lesions56 strongly suggest that deficits in vestibulocerebellar function may play a role in this movement disorder. Because the cerebellum is required for adaptive gain modification of both the blink57 and vestibulo-ocular58 reflexes, it would be reasonable to assume that olivocerebellar dysfunction could explain the physiological abnormalities detected in patients with primary cervical dystonia. Many investigators, however, have provided practical explanations for these physiological abnormalities based on dysfunction of the basal ganglia. Rather than implicating any particular local-area network, functional imaging in patients with cervical dystonia, generalized dystonia,5 and blepharospasm7 presents, instead, a complex pathophysiological picture of dystonia that presents the possibility of substantial interactions between olivocerebellar and basal gangliathalamocortical circuits. In cervical dystonia, hypermetabolism was found in the basal ganglia, thalamus, premotor–motor cortex, and cerebellum.59 A similar pattern of hypermetabolism was detected in both manifesting and nonmanifesting carriers of DYT1 mutations.5 In movement-free conditions, both manifesting and nonmanifesting carriers showed increased metabolic activity in the lentiform nuclei, cerebellum, and supplementary motor areas. In movement-related conditions, manifesting carriers showed increased metabolic activity in the midbrain, cerebellum, and thalamus. Anatomical and physiological interactions between the olivocerebellar and basal ganglia-thalamocortical circuits that have been demonstrated in both rodents and primates provide considerable insight into mechanisms potentially operative in cervical dystonia. For example, it has been shown that primary motor cortex is the transneuronal target of somatotopically organized outputs from both the cerebellum and basal ganglia.60 Approximately 30% of neurons in the dentate nucleus and 15% of neurons in the internal segment of the globus pallidus project transneuronally to primary motor cortex via the thalamus. These projections terminate in overlapping fields onto specific motor representations within primary motor cortex. The cerebellum also sends projections to 67 several prefrontal regions via the thalamus.61 Transneuronal projections from the basal ganglia terminate in some of the same regions as those from the cerebellum.62 Terminals fields from the basal ganglia and cerebellum also overlap at subcortical sites. For example, the cerebello-tectal projection from the rat interpositus nucleus overlaps with terminals from the nigrotectal pathway originating in the dorsolateral substantia nigra pars reticulata.63 These results suggest that: 1) olivocerebellar dysfunction can alter the physiology and metabolic topography of the basal ganglia-thalamocortical network22; 2) abnormalities of olivocerebellar and basal gangliathalamocortical circuits may, in some situations, produce similar movement disorders; and 3) the appearance of cervical dystonia, although due to a primary olivocerebellar abnormality, may require interaction between the olivocerebellar and basal ganglia-thalamocortical networks. Secondary cervical dystonia associated with structural lesions of the CNS is much less common than nondystonic causes of torticollis. Abnormal head posturing in neonates and children should be considered nondystonic until proven otherwise. Adults with abnormal head postures that present with other neurological abnormalities or features atypical for idiopathic dystonia such as failure to improve with sleep, severe pain, headaches, nausea, or vertigo should undergo imaging of the brain and cervical spine. Acknowledgments: M.S.L. was supported, in part, by the Society for Progressive Supranuclear Palsy, Benign Essential Blepharospasm Research Foundation, and the National Eye Institute (RO1-EY-12232). REFERENCES 1. Nutt JF, Muenter MD, Aronson A, Kurland LT, Melton LJ III. Epidemiology of focal and generalized dystonia in Rochester, Minnesota. Mov Disord 1988;3:188 –194. 2. The Epidemiological Study of Dystonia in Europe (ESDE) Collaborative Group. A prevalence study of dystonia in Europe (ESDE) collaborative group. J Neurol 2000;247:787–792. 3. Fahn S, Marsden CD, Calne DB. Classification and investigation of dystonia. In: Marsden CD, Fahn S, editors. Movement disorders 2. London: Butterworth; 1987. p 332–358. 4. Fahn S, Bressman SB, Marsden CD. Classification of dystonia. In: Fahn S, Marsden CD, DeLong M, editors. Dystonia 3. Advances in neurology, Vol. 78. Philadelphia, PA: Lippincott-Raven Publishers; 1998. p 1–10. 5. Eidelberg D, Moeller JR, Antonini A, et al. Functional brain networks in DYT1 dystonia. Ann Neurol 1998;44:303–312. 6. Perlmutter JS, Stambuk MK, Markham J, et al. Decreased [18F] spiperone binding in putamen in dystonia. In: Fahn S, Marsden CD, DeLong M, editors. Dystonia 3. Advances in neurology. Vol. 78. Philadelphia: Lippincott-Raven; 1998. p 161–168. 7. Hutchinson M, Nakamura T, Moeller JR, et al. The metabolic topography of essential blepharospasm: a focal dystonia with general implications. Neurology 2000;12:673– 677. Movement Disorders, Vol. 18, No. 1, 2003 68 M.S. LEDOUX AND K.A. BRADY 8. Lenz FA, Jaeger CJ, Seike MS, et al. Thalamic single neuron activity in patients with dystonia: dystonia-related activity and somatic sensory reorganization. J Neurophysiol 1999;82:2372– 2392. 9. Vitek JL, Chockkan V, Zhang JY, et al. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999;46:22–35. 10. Schicatano EJ, Basso MA, Evinger C. Animal model explains the origins of the cranial dystonia benign essential blepharospasm. J Neurophysiol 1997;77:2842–2846. 11. LeDoux MS, Lorden JF. Abnormal cerebellar output in the genetically dystonic rat. In: Fahn S, Marsden CD, DeLong M, editors. Dystonia 3. Advances in neurology. Vol. 78. Philadelphia, PA: Lippincott-Raven; 1998. p 63–78. 12. Konakova M, Huynh DP, Yong W, Pulst SM. Cellular distribution of torsin A and torsin B in normal human brain. Arch Neurol 2001;58:921–927. 13. Jankovic J, Patel SC. Blepharospasm associated with brainstem lesions. Neurology 1983;33:1237–1240. 14. Marsden CD, Obeso JA, Sarranz JJ, Lang AE. The anatomical basis of symptomatic hemidystonia. Brain 1985;108:463– 483. 15. Lee MS, Marsden CD. Movement disorders following lesions of the thalamus or subthalamic region. Mov Disord 1994;9:493–507. 16. Siebold C, Kleine JF, Glonti L, Tchelidze T, Buttner U. Fastigial nucleus activity during different frequencies and orientations of vertical vestibular stimulation in the monkey. J Neurophysiol 1999;82:34 – 41. 17. Manzoni D, Pompeiano O, Bruschini L, Andre P. Neck input modifies the reference frame for coding labyrinthine signals in the cerebellar vermis: a cellular analysis. Neuroscience 1999;93:1095– 1107. 18. Brain WR. On the rotated or “cerebellar” posture of the head. Brain 1926;49:61–76. 19. Suchowersky O, Calne DB. Nondystonic causes of torticollis. In: Fahn S, Marsden CD, Calne DB, editors. Dystonia 2. Advances in neurology. Vol. 50. New York: Raven-Press; 1988. p 501–508. 20. Calne DB, Lang AE. Secondary dystonia. In: Fahn S, Marsden CD, Calne DB, editors. Dystonia 2. Advances in neurology. Vol. 50. New York: Raven-Press; 1988. p 9 –33. 21. Boisen E. Torticollis caused by an infratentorial tumour: three cases. Br J Psychiatry 1979;134:306 –307. 22. Tranchant C, Maquet J, Eber AM, Dietemann JL, Franck P, Warter JM. Cerebellar cavernous angioma, cervical dystonia and crossed cortical diaschisis. Rev Neurol 1991;147:599 – 602. 23. Krause JK, Seeger W, Jankovic J. Cervical dystonia associated with tumors of the posterior fossa. Mov Disord 1997;12:443– 447. 24. Caress JB, Nohria V, Fuchs H, Boustany RM. Torticollis acquired in late infancy due to a cerebellar gangliocytoma. Mov Disord 1996;36:39 – 44. 25. Plant GT, Kermode AG, du Boulay EPGH, McDonald WI. Spasmodic torticollis due to a midbrain lesion in a case of multiple sclerosis. Mov Disord 1989;4:359 –362. 26. Soland V, Evoy F, Rivest J. Cervical dystonia due to a frontal meningioma. Mov Disord 1996;11:336 –337. 27. Kiwak KJ, Deray MJ, Shields WD. Torticollis in three children with syringomyelia and spinal cord tumor. Neurology 1983;33: 946 –948. 28. Klostermann W, Vieregge P, Kompf D. Spasmodic torticollis in multiple sclerosis: significance of an upper cervical spinal cord lesion. Mov Disord 1993;8:234 –236. 29. Cammerota A, Gershanik OS, Garcia S, Lera G. Cervical dystonia due to a spinal cord ependymoma: involvement of spinal cord segments in the pathogenesis of dystonia. Mov Disord 1995;10: 500 –503. 30. Hill MD, Kumar R, Lozanzo A, Tator CH, Ashby P, Lang AE. Syringomyelic dystonia and athetosis. Mov Disord 1999;14:684 – 688. 31. Isaac K, Cohen JA. Post-traumatic torticollis. Neurology 1989;39: 1642–1643. Movement Disorders, Vol. 18, No. 1, 2003 32. Molho ES, Factor SA. Basal ganglia infarction as a possible cause of cervical dystonia. Mov Disord 1993;8:213–216. 33. Schulz-Bunhage A, Ferbert A. Cervical dystonia as an isolated sign of a basal ganglia tumour. J Neurol Neurosurg Psychiatry 1995; 58:108 –109. 34. Schwartz M, DeDeyn PP, Van den Kerchove M, Pickut BA. Cervical dystonia as a probable consequence of a focal cerebral lesion. Mov Disord 1995;10:797–798. 35. Stratton SE, Lorden JF. Effect of harmaline on cells of the inferior olive in the absence of tremor: differential response of genetically dystonic and harmaline-tolerant rats. Neuroscience 1991;41:543– 549. 36. LeDoux MS, Hurst DC, Lorden JF. Single-unit activity of cerebellar nuclear cells in the awake genetically dystonic rat. Neuroscience 1998;86:533–545. 37. LeDoux MS. Harmaline-stimulated fos-immunoreactivity in the genetically dystonic rat. Mov Disord 2000;15(Suppl. 3):161. 38. LeDoux MS, Lorden JF. Abnormal spontaneous and harmalinestimulated Purkinje cell activity in the genetically dystonic rat. Exp Brain Res 2002;145:457– 467. 39. Sukin D, Skedros DG, Beales M, Stratton SE, Lorden JF, Oltmans GA. Temporal sequence of motor disturbances and increased cerebellar glutamic acid decarboxylase activity following 3-acetylpyridine lesions in adult rats. Brain Res 1987; 426:82–92. 40. Campbell DB, North JB, Hess EJ. Tottering mouse motor dysfunction is abolished on the Purkinje cell degeneration (pcd) mutant background. Exp Neurol 1999;160:268 –278. 41. Walberg F. Descending connections to the inferior olive: an experimental study in the cat. J Comp Neurol 1956;104:77–173. 42. Berkley KJ, Hand PJ. Projections to the inferior olive of the cat. II. Comparisons of input from the gracile, cuneate and the spinal trigeminal nuclei. J Comp Neurol 1978;180:253–264. 43. Berkley KJ, Worden IG. Projections to the inferior olive of the cat. I. Comparisons of input from the dorsal column nuclei, the lateral cervical nucleus, the spino-olivary pathways, the cerebral cortex and the cerebellum. J Comp Neurol 1978;180:237–252. 44. Swenson RS, Castro AJ. The afferent connections of the inferior olivary complex in rats. An anterograde study using autoradiographic and axonal degeneration techniques. Neuroscience 1983; 8:259 –275. 45. Mettler FA. The tegmento-olivary and central tegmental fasciculi. J Comp Neurol 1944;80:149 –175. 46. Walberg F. Descending connections from the mesencephalon to the inferior olive: an experimental study in the cat. Exp Brain Res 1974;21:145–156. 47. Saint-Cyr JA, Courville J. Sources of descending afferents to the inferior olive from the upper brainstem in the cat as revealed by the retrograde transport of horseradish peroxidase. J Comp Neurol 1981;198:567–581. 48. Carrea RME, Mettler FA. Function of the primate brachium conjunctivum and related structures. J Comp Neurol 1955;102:565– 689. 49. Carpenter MB. A study of the red nucleus in the rhesus monkey. Anatomic degeneration and physiological effects resulting from localized lesions in the red nucleus. J Comp Neurol 1956;105:195– 249. 50. Foltz El, Knopp LM, Ward AA. Experimental spasmodic torticollis. J Neurosurg 1959;16:55–72. 51. Nakazawa M, Kobayashi T, Matsuno K, Mita S. Possible involvement of a sigma receptor subtype in the neck dystonia in rats. Pharmacol Biochem Behav 1999;62:123–126. 52. Lew H, Jordan C, Jerger J, Jankovic J. Acoustic reflex abnormalities in cranial– cervical dystonia. Neurology 1992;42:594 –597. 53. Pauletti G, Berardelli A, Cruccu G, Agostino R, Manfredi M. Blink reflex and the masseter inhibitory reflex in patients with dystonia. Mov Disord 1993;8:495–500. SECONDARY CERVICAL DYSTONIA 54. Münchau A, Corna S, Gresty MA, et al. Abnormal interaction between vestibular and voluntary head control in patients with spasmodic torticollis. Brain 2001;124:47–59. 55. Huygen PL, Verhagen WI, Van Hoof JJ, Horstink MW. Vestibular hyperreactivity in patients with idiopathic spasmodic torticollis. J Neurol Neurosurg Psychiatry 1989;52:782–785. 56. Bronstein AM, Rudge P, Beechey AH. Spasmodic torticollis following unilateral VIII nerve lesions: neck EMG modulation in response to vestibular stimuli. J Neurol Neurosurg Psychiatry 1987;50:580 –586. 57. Evinger C, Pellegrini JJ, Manning KA. Adaptive gain modification of the blink reflex. A model system for investigating the physiologic bases for motor learning. Ann NY Acad Sci 1989;563:87– 100. 58. Robinson DA. Adaptive gain control of vestibuloocular reflex by the cerebellum. J Neurophysiol 1976;39:954 –969. 69 59. Galardi G, Perani D, Grassi F, et al. Basal ganglia and thalamocortical hypermetabolism in patients with spasmodic torticollis. Acta Neurol Scand 1996;94:172–176. 60. Hoover JE, Strick PL. The organization of cerebellar and basal ganglia outputs to primary motor cortex as revealed by retrograde transneuronal transport of herpes simplex virus type 1. J Neurosci 1999;19:1446 –1463. 61. Middleton FA, Strick PL. Cerebellar projections to the prefrontal cortex of the primate. J Neurosci 2001;21:700 –712. 62. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986;9:357–381. 63. Westby GW, Collinson C, Dean P. Excitatory drive from deep cerebellar neurons to the superior colliculus in the rat: an electrophysiological mapping study. Eur J Neurosci 1993;5:1378 –1388. Movement Disorders, Vol. 18, No. 1, 2003