Delayed-Onset Cerebellar Syndrome Elan D. Louis, MD, MS; Timothy Lynch, MRCPI; Blair Ford, MD, MRCP; Paul Greene, MD; Susan B. Bressman, MD; Stanley Fahn, MD Background: Delayed-onset involuntary movements, including dystonia and myoclonus, have been reported after stroke or head trauma. Moreover, there have been reports of delayed-onset isolated intention tremor and, in several of these cases, gait ataxia. Objective: To further define the clinical features of a delayed-onset cerebellar syndrome. Design: Subjects with cerebellar tremor and either head trauma or stroke were identified using a computerized database, providing detailed demographic and clinical in- formation on 4002 patients with involuntary move- ments other than Parkinson's disease seen at our center between 1983 and 1995. Medical records and video- taped neurological examinations were retrospectively re- viewed. Setting: The Center for Parkinson's Disease and Other Movement Disorders at Columbia-Presbyterian Medical Center, New York, NY. Patients: Five patients with delayed-onset cerebellar syndromes. Results: Five patients with stroke or head trauma developed a cerebellar syndrome 3 weeks to 2 years after the initial insult. The syndrome, characterized by intention tremor, ataxic dysarthria, nystagmus, dysmetria, dysdiadochokinesis, and gait ataxia, was progressive in at least one patient. In four patients, lesions were present on neuroimaging in the thalamus or brain stem (especially in the midbrain). Conclusions: A delayed-onset cerebellar syndrome may follow head trauma or stroke. The syndrome is sometimes progressive and often disabling. The delayed onset implies that the syndrome is not caused by the initial lesion itself but may be caused by the development of post\x=req-\ synaptic supersensitivity or secondary reorganization of involved pathways. DELAYED-ONSET (Arch Neurol. 1996;53:450-454) involun¬ tary movements have been reported either in the setting of therapeu¬ tic use of neuroleptic agents (ie, tardive dyskinesia and tardive dystonia)1·2 or following stroke or head trauma (ie, palatal myoclonus, dystonia, poststroke tremor at rest).3'7 There have been reports of delayed- onset isolated intention tremor; several of these cases also exhibited gait ataxia.8·9 We describe five patients with stroke or head trauma who subse¬ From the Department of Neurology (Drs Louis, Lynch, Ford, Greene, Bressman, and Fahn) and the Gertrude H. Sergievsky Center (Dr Louis), Columbia University College of Physicians and Surgeons, New York, NY. quently developed a delayed-onset cer¬ ebellar syndrome characterized by intention tremor as well as ataxic dysar¬ thria, nystagmus, dysmetria, dysdiado- REPORT OF A CASE A previously healthy 13-year-old right- handed boy (patient 1) sustained head trauma in a motor vehicle accident. The patient lost consciousness, and in the emergency department, he exhibited decerebrate posturing; his Glasgow Coma Scale score was 6. He required ventilator assistance. Computed tomography of the head revealed a hematoma in the left su¬ perior mesial thalamus and increased in¬ tracranial pressure without shift of midline structures. The patient was initially in a coma, but 12 days after trauma, he be¬ came responsive to verbal stimuli. Five weeks after trauma, examination dis- chokinesis, and gait ataxia. The purpose of this article is to add our cases to the literature and to further define other clinical features of a delayed-onset cer¬ ebellar syndrome. Downloaded From: http://archneur.jamanetwork.com/ by a Western University User on 06/08/2015 See Subjects amd Methods on next page SUBJECTS AND METHODS The study population consisted of patients with in¬ voluntary movement disorders evaluated at the Cen¬ ter for Parkinson's Disease and Other Movement Dis¬ orders at Columbia-Presbyterian Medical Center, New York, NY, between October 1983 and June 1995. Sub¬ jects were identified using a computerized database, providing detailed demographic and clinical infor¬ mation on 4002 patients with involuntary move¬ ments other than Parkinson's disease. Subjects were located by searching for the key terms cerebellar dis¬ order, cerebellar-type tremor, trauma, or stroke. Eleven patients were identified with cerebellar syndromes following stroke or trauma. Six were excluded be¬ cause we could not definitively document that cer¬ ebellar signs had a delayed onset. Five patients were included (Table). One case is described in detail. Neurological status was assessed at three se¬ quential intervals: time 0, the time of the initial in¬ sult (head trauma or stroke); time 1, soon after the return to baseline level of consciousness (in cases in which there was an initial reduction in level of con¬ sciousness); and time 2, the time of initial examina¬ tion by a movement disorder specialist at our center (Table). In addition, four of the patients were exam¬ ined by a movement disorder specialist at our center on one or more occasions after time 2. Videotaped neurological examinations (performed at time 2) and hospital records (providing clinical information about times 0 and 1) were reviewed for all five patients. Standard definitions were used: Intention tremor was defined as oscillatory movements present on the finger-to-nose maneuver that became more appar¬ ent as fine adjustments in movement were required or as a target was approached. Dysmetria was de¬ fined as inappropriate force and timing of motion characterized by either hypermetria or hypometria and demonstrated on the finger-to-nose or heel-toshin maneuver. Dysdiadochokinesis was defined as a disorder of rhythmicity affecting volitional rapid al¬ ternating movements of the limbs. Rebound was de¬ fined as contraction of extensor antagonists after re¬ lease of the arm flexed at the elbow. Gait ataxia was defined as a poorly coordinated, unsteady, lurching, wide-based gait; and truncal ataxia was defined as poorly coordinated and unsteady truncal move¬ ments and posture. Ataxic dysarthria was defined as slow, monotonous, slurred speech with unnatural separation of syllables.10"12 closed an alert, attentive boy who had difficulty with re¬ call and simple calculations, right trochlear nerve palsy, and mild left-sided weakness. He was ambulatory and ate pureed food. Six weeks after trauma, he first developed a mild right-handed tremor, noted with handwriting and fine finger manipulations. The tremor gradually spread to his arm and shoulder, and the severity increased markedly. He was first evaluated at Columbia-Presbytrian Medi¬ cal Center 21 months after trauma. His major complaint was right arm tremor, which made handwriting virtu- ally impossible and significantly impaired his ability to perform activities of daily living, including eating, dress¬ ing, and bathing. On examination, he was alert and at¬ tentive but had difficulty with calculations, recall, and copying figures. Speech was fluent but characterized by ataxic dysarthria. There was horizontal nystagmus on lat¬ eral gaze, with the fast component contralateral to the direction of gaze. There was right trochlear nerve palsy, upper motor neuron facial weakness on the left side, and mild left-sided hemiparesis (Medical Research Council score, 4) with hypertonicity. On finger-to-nose testing, there was a severe, violent, right-sided intention tremor. There was dysmetria on the right side on both finger-tonose and heel-to-shin testing. Rebound was diminished on the right side. His handwriting was almost illegible because of the severity of the tremor. Tremor analysis (accelerometric leads and surface electromyographic electrodes positioned over proximal and distal arm muscles) was consistent with a cerebellar tremor, revealing a low-frequency (1.5 to 4 Hz) tremor with action that was characterized by a high relative am¬ plitude on finger-to-nose testing in comparison with arm sustentation. A magnetic resonance imaging study 4 months after trauma revealed an old hematoma in the left superior mesial thalamus and ischemie changes in the right pons extending into the midbrain (Figure 1, Figure 2, and Figure 3). Botulinum toxin injections on three occasions into the right pronator muscle of the forearm and the right wrist flexors and extensors did not diminish the tremor or dysmetria. RESULTS Five patients developed a delayed-onset cerebellar syn¬ drome: three after head trauma, one after intracerebral hemorrhage, and one after basilar aneurysm with midbrain compression and thalamic infarction (Table). Cer¬ ebellar signs included dysmetria (n=5), intention tremor (n=5), dysdiadochokinesis (n=4), ataxic dysarthria (n=4), ataxic gait or truncal ataxia (n=3), and nystagmus (n=3). One patient had diminished rebound; this sign was not consistently coded as present or absent in the remain¬ ing medical records. Cerebellar symptoms and signs de¬ veloped between 3 weeks and 2 years after head trauma or stroke (mean, 38 weeks). In two cases (patients 2 and 3), the cerebellar syndrome was bilateral but more se¬ vere contralateral to mild weakness. In one case (pa¬ tient 5), the cerebellar syndrome and corticospinal tract signs were both bilateral. In the remaining two cases (pa¬ tients 1 and 4), the cerebellar syndrome was unilateral, in one case contralateral to mild weakness and in the other case ipsilateral. Three subjects initially had severe hemi¬ paresis, but at the time of their visit to our center, all five patients had a Medical Research Council score of 4 or greater. Two of the patients had mild hemisensory ab¬ normalities on examination; in one (patient 4), dimin¬ ished light touch and pain were ipsilateral to the cer¬ ebellar signs but far too mild and patchy to account for the degree of dysmetria. The three patients with head trauma had been comatose for 2 days to 2 months (mean, Downloaded From: http://archneur.jamanetwork.com/ by a Western University User on 06/08/2015 Clinical Features of Delayed-Onset Cerebellar Syndrome* Patient No./ Age at Onset, yf/ Sex 1/13/M 2/19/M Cause Head trauma Head trauma Timing of CT and MRI* CT within 24 h, MRI at 4 mo CT within 24 h, MRI at 4.5 y CT or MRI Lesions L thalamic (superior Neurologic Statusj Delay§ Time 0 Time 1 6 wk Comatose, decerebrate posturing, ventilator 5 wk after insult: L-sided weakness, R cranial nerve IV palsy, mild cognitive mesial) hemorrhage, R pons/mldbrain (anterior) ischemie changes L thalamic (inferior posterior/mesial) hemorrhage, assistance deficit, ambulatory, pureed food iy Comatose, ventilator 4-6 mo after insult: L-sided weakness, disinhibited behavior, mild cognitive deficit, ambulatory, normal diet 2y Comatose 2 mo after insult: L-sided weakness, L hemisensory assistance L midbrain infarct (posterior), mild diffuse cortical 3/25/M Head trauma CT and MRI at 5 y atrophy Mild diffuse cortical atrophy deficit, ambulatory, normal diet 4/71/F 5/67/F Stroke/hemorrhage CT within 24 h and at 6 mo R thalamic (superior 6 mo Basilar aneurysm with bilateral midbrain compression and R thalamic infarct; surgical resection 5 wk after onset of cerebellar syndrome CT at 2 mo R thalamic (inferior 3wk centrolateral) hemorrhage anterior-mesial) infarct and bilateral midbrain (anterior) compression L-sided weakness, L hemisensory deficit Not applicable, patient 4-Limb weakness (L>R), R cranial nerve III palsy, L cranial nerve VI Not applicable, patient never comatose never comatose palsy *CT indicates computed tomography; MRI, magnetic resonance imaging. -\Age at onset of cerebellar syndrome. i Time between insult and imaging study. § Time between insult and onset of cerebellar syndrome. \\Time 0 was the time of Initial Insult; time 1, soon after return to the baseline level of consciousness; and time 2, when seen at our center. Figure 1. A follow-up T¡-weighted head magnetic resonance image 4 months after trauma reveals an old hematoma in the left superior-mesial-central thalamus. Pencil mark Figure 2. A follow-up T2-weighted head magnetic resonance image 4 months after trauma reveals ischemie changes in the right midbrain. indicates the left thalamus and lentiform nucleus. Downloaded From: http://archneur.jamanetwork.com/ by a Western University User on 06/08/2015 Figure 3. A follow-up T2-weighted head magnetic resonance image 4 months after trauma reveals Ischemie changes In the right pons. Pencil mark indicates the right pons and cerebellum. All patients had either head computed tomography magnetic resonance imaging. Lesions were present in both the thalamus and midbrain in two patients; in the thalamus, midbrain, and pons in one patient; and in the thalamus alone in one patient. Different regions of the or Time 2 1 y after insult: L-sided weakness, R cranial nerve IV palsy, mild cognitive deficit, ambulatory, "I Cerebellar Syndrome Ataxic dysarthria, nystagmus, R dysmetria, R intention tremor, R diminished rebound normal diet 4.5 y after Insult: Ataxic dysarthria, L-sided weakness, nystagmus, bilateral cranial R>L dysmetria, nerve X palsy, mild R>L intention tremor, cognitive deficit, R>L dysdiadochokinesis, ataxic gait ambulatory, normal diet 5 y after insult: Ataxic dysarthria, bilateral L-sided weakness, nystagmus, L hemisensory R>L dysmetria, R>L intention tremor, deficit, torticollis, R>L dysdiadochokinesis, ambulatory, normal diet ataxic gait 6 mo after insult: L dysmetria, L intention L-sided weakness, tremor, L dysdiadochokinesis, L hemisensory deficit, chorea ataxic gait (L arm) 5 mo after insult: 4-limb weakness (L>R), R cranial nerve III palsy, L cranial nerve VI Ataxic dysarthria, R>L dysmetria, R>L intention tremor, R>L dysdiadochokinesis Treatment Three botulinum toxin injections into R forearm thalamus and midbrain were involved in each case. Two patients also had diffuse cortical atrophy. On follow-up imaging studies, no evolving changes correlated with pro¬ gression of neurological deficits. COMMENT Propranolol, primidone, baclofen, clonazepam, carbamazepine, L sterotactic thalamotomy L sterotactic thalamotomy Levodopa/ carbidopa, tetrabenazine None palsy 24.7 days). None of the patients had a family history of cerebellar disorder. In four cases, "tremor" was the patient's chief com¬ plaint and reason for initial evaluation at ColumbiaPresbyterian Medical Center. At the point of greatest se¬ verity, all of the patients were unable to perform at least one activity of daily living (feeding, dressing, or bath¬ ing) as a result of their tremor. In two cases (patients 1 and 5), the symptoms worsened over 4 to 7 months and then reached a plateau. In one case (patient 2), symp¬ toms worsened over 3.5 years prior to a unilateral stereotactic thalamotomy. The thalamotomy provided par¬ tial relief of the tremor, and the syndrome did not progress over the ensuing 4 months. In one case (patient 3), symp¬ toms worsened over 3 years prior to a unilateral stereotactic thalamotomy. The thalamotomy provided partial relief of the tremor, but the dysmetria continued to progress during the ensuing 3-year period. One patient (patient 1) received botulinum toxin injections into the tremulous arm, and two others received medical treat¬ ment. There was no change in the tremor or dysmetria. Delayed-onset intention tremor without other associ¬ ated cerebellar signs has been reported after mild head trauma with normal findings on neuroimaging stud¬ ies,13 after infarctions in the thalamus or frontal lobe, and after hemorrhages in the thalamus, parieto-occipital lobe, or pons.14"18 Ghika et al19 described three patients with delayed-onset complex hyperkinetic motor syndromes (dystonia, myoclonus, chorea, rubral tremor, and ataxia) after thalamic infarctions. Andrew et al8 reported eight cases of intention tremor 2.2 to 14 years after head trauma. One of these patients had gait ataxia, but head com¬ puted tomography did not reveal a focal abnormality. Iwadate et al9 reported eight cases of intention tremor 2 to 16 weeks after head trauma. Four of these patients had midbrain hematomas on head computed tomography; two had gait ataxia. The literature on delayed-onset inten¬ tion tremor does not emphasize the presence of other cer¬ ebellar signs.13"18 We report five cases of a delayed-onset cerebellar syndrome characterized not only by inten¬ tion tremor but also by other cerebellar findings, includ¬ ing nystagmus, ataxic dysarthria, dysmetria, and dysdi¬ adochokinesis. The syndrome was disabling and in at least one of the cases, also progressive. On neuroimaging, four patients had lesions in the thalamus or brain stem (especially in the midbrain), and the cerebellar syndrome was presumably caused by these lesions, although it is possible that some cases may have had additional brain-stem infarcts that were not seen. The topographic distribution of lesions within the thalamus and midbrain was not uniform, making precise clinical-anatomical correlation difficult (Table). Iwadate et al9 hypothesized that posttraumatic intention tremor may be caused by disruption of cer¬ ebellar outflow pathways in the brain stem, particu¬ larly the dentato-rubro-thalamic pathway. LaRochelle et al20 demonstrated that intention tremor may be pro¬ duced experimentally in monkeys by creating lesions in the dentato-rubro-olivary pathways. The cerebellar syndrome was delayed and some¬ times progressive, implying that it may not be attribut¬ able to the initial lesion itself. Acute cerebellar strokes and experimental ablation of areas of cerebellar cortex and deep cerebellar nuclei typically result in cerebellar signs of immediate onset that improve over days to weeks.21"23 Occasionally, signs from cerebellar strokes de¬ velop after 2 to 5 days, possibly secondary to an evolv¬ ing embolie cause.24 The prolonged delay in our cases may have been caused by the development of postsynaptic supersensitivity in involved brain-stem or thalamic path¬ ways. Delayed-onset palatal myoclonus has been attrib- Downloaded From: http://archneur.jamanetwork.com/ by a Western University User on 06/08/2015 uted to the development of postsynaptic supersensitivity after decentralization of the inferior olivary nucleus by lesions in the dentato-rubro-olivary system.' Alterna¬ tively, the syndrome may have been caused by second¬ ary reorganization of cerebelar outflow or thalamic path¬ ways.14 Ohye et al25 observed changes in electrical activity in and around the thalamus (nucleus ventralis intermedius) in patients with poststroke action tremor, sup¬ porting the notion of a reorganization of thalamic nuclei following stroke. In a positron emission tomog¬ raphy study, Weiller et al26 reported functional reorga¬ nization of the contralateral cerebellum in the recov¬ ery phase following stroke. Serial postiron emission tomography studies might have helped to clarify the mechanism of delayed onset in our cases. While some of our patients had mild weakness (Medical Research Council score &4) or sensory defi¬ cits, either cerebellar signs were present in contralateral limbs (cases 1 through 3) or the pyramidal or sensory signs (slight, patchy diminution in pain and tempera¬ ture sense) were inadequate to account for the almost bal¬ listic severity of the dysmetria (cases 4 and 5). It is unlikely that severe weakness masked early cerebellar signs, since in those with severe initial weakness (cases 1 through 3), cerebellar signs were contralateral to weak limbs. In the patients with posttraumatic syn¬ dromes, it is unlikely that earlier cerebellar signs were masked by coma, as cerebellar signs were initially noted 1 week to 22 months after return to baseline level of consciousness, while patients were ambulatory and eating normal diets. In fact, we excluded six patients because it was unclear from review of medical records whether the cerebellar signs had a delayed onset; they may have begun while consciousness was still impaired. In summary, we report five cases of a delayedonset cerebellar syndrome characterized by intention tremor, ataxic dysarthria, nystagmus, dysmetria, dysdi¬ adochokinesis, and gait ataxia. The syndrome is some¬ times progressive and often severely disabling. The fre¬ quency of this syndrome is difficult to estimate. While it present in one of 800 patients with nonparkinsonian involuntary movements seen at our center, imply¬ ing that it is rare, the syndrome may be more common in head injury or stroke databases. On neuroimaging, le¬ sions are present in the thalamus or brain stem (espe¬ cially in the midbrain), with possible disruption of the dentato-rubro-thalamic or dentato-rubro-olivary path¬ ways. The delayed onset and progression imply that the syndrome is not caused by the initial lesion itself, but possibly by the development of postsynaptic was supersensitivity involved pathways. or secondary reorganization of Accepted for publication February 1, 1996. This work was supported by grant NS010863 from the National Institutes of Health, Bethesda, Md. Reprint requests to Unit 198, Neurologic Institute of New York, 710 W 168th St, New York, NY 10032 (Dr Louis). REFERENCES 1. Sigwald J, Bouttier D, Raymondeaud C, Piot C. Quatre cas de dyskin\l=e'\siefaciobucco-linguo-masticatrice \l=a`\l'\l=e'\volutionprolong\l=e'\esecondaire \l=a`\un traitement par les neuroleptiques. Rev Neurol Paris. 1959;100:751-755. 2. Kang JU, Burke RE, Fahn S. Natural history and treatment of tardive dystonia. Mov Disord. 1986;1:193-208. 3. Brett EM, Sheehy MP. Progressive hemi-dystonia due to focal basal ganglia lesion after mild head trauma. J Neurol Neurosurg Psychiatry. 1981;44:460. 4. 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