Paraneoplastic “rubral” tremor: A case report

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Discussion Dystonic storm is a condition of severe, potentially lifethreatening, generalized dystonia arising precipitously, often against a backdrop of chronic dystonia. Dystonic storm may be caused by trauma, surgery, infection, fever, medication withdrawal, or, as in the present case, no clear precipitant. We follow another patient who experienced dystonic storm after the abrupt cessation of ITB therapy, described as a complication in a previous report4 The differential diagnosis of dystonic storm includes malignant hyperthermia and neuroleptic malignant syndrome. The immediate risks to life in this setting include hyperthermia, muscular fatigue, rhabdomyolysis with acute renal failure,’,6 dehydration, and respiratory compromise. Dystonic storm should be treated in an intensive-care unit. Treatment consists of supportive measures, including hydration, pain control, monitoring, respiratory assistance if needed, and attempts to interrupt the intractable dystonic spasms.’ Hyperpyrexia may respond to acetaminophen or require external cooling. Myoglobinuria requires adequate hydration but dialysis may be needed.2 To reduce the dystonic spasms, several oral medications in high doses have been suggested.’ Agents such as dantrolene, tetrabenazine, and neuroleptics may be tried on an empiric basis, titrating to a state of parkinsonism or weakness. Clozapine has been used for intractable tardive dystonia’ and may also be considered in dystonic storm. Intravenous muscle relaxants and sedatives are useful as an intermediate step before skeletal muscle paralysis with pancuronium’ or general anesthesia using thiopental or propafol.’ However, as previous reports’ and the current case indicate, there is a tendency for intractable dystonia to recur on withdrawal of sedating, paralyzing, or anesthetic agents. As shown in our report, ITB may be effective in the treatment of dystonic storm and may obviate the need for general anesthesia. The technique can be effective in treating intractable dystonia4 and in fact has been used in cases that would qualify as dystonic In an intensive-care unit, ITB titration can be more rapidly performed than is possible in the ward or ambulatory setting. ITB can interrupt the dystonic spasms and, after implantation of a pump, offers the possibility of chronic maintenance therapy: an advantage over intravenous medication. In the initial phase of treating dystonic storm, adjustments in oral medication and the use of a titratable intravenous agent such as midazolam may help facilitate a smooth reduction in dystonia as the ITB dosage is adjusted. In the long-term, ITB therapy is often limited by the development of tolerance,” especially in d y ~ t o n i aDeclining .~ efficacy may necessitate an assessment of pump function, dose adjustment, drug holiday, or medication substitution”; in chronic refractory cases of generalized dystonia, stereotactic thalamotomy or pall i d o t ~ m y may ’ ~ be considered, as in the present case. In the acute and life-threatening setting of dystonic storm, however, ITB offers an important, safe, and rapidly acting therapeutic intervention.

Arif Dalvi, MD Department of Neurology University of Cincinnati Cincinnati, Ohio,U.S.A. Stanley Fahn, MD Blair Ford, MD Department of Neurology Columbia University New York, NY, U.S.A.

References 1. Fahn S. Concept and classification of dystonia. Adv Neurol 1988;

50:1-8. 2. Vaamonde J, Narbona J , Weiser R, Garcia MA, Brannan T, Obeso JA. Dystonic storms: a practical management problem. Clin Neuropharmucol 1994;17:344-347. 3. Burke RE, Fahn S, Marsden CD, Bressman SB, Moskowitz C, Friedman J. Validity and reliability of a rating scale for the primary torsion dystonias. Neurology 1985;35:73-77. 4. Ford B, Greene P, Louis ED, et al. Use of intrathecal baclofen in the treatment of patients with dystonia. Arch Neurol 1996;53: 1241-1246. 5. Jankovic J, Penn AS. Severe dystonia and myoglobinuria. Neurology 1982132:1195-1197. 6. Paret G, Tirosh R, Ben-Zeev B, Vardi A, Brandt N, Barzilay Z. Rhabdomyolysis due to hereditary torsion dystonia. Pediatr Neurol 1995;13:83-84. 7. Trugman JM, Leadbetter R, Zallis ME, Burgdorf RO, Wooten GF. Treatment of severe axial tardive dystonia with clozapine: case report and hypothesis. Mov Disord 1994;9:441446. 8. Narayan RK, Loubser MB, Jankovic J, Donovan WH, Bontke CF. Intrathecal baclofen for intractable axial dystonia. Neurology 1991; 41:1141-1142. 9. Delhaas EM, Brouwers JRBJ. Intrathecal baclofen overdose: report of 7 events in 5 patients and review of the literature. Znr J Clin Pharrnacol Ther 1991;29:274-280. 10. Akman MN, Loubser PG, Donovan WH, O’Neill ME, Rossi CD. Intrathecal baclofen: does tolerance occur? Paruplegia 1993;31: 5 16-520. 11. Chabal C, Jacobson L, Terinan G. Intrathecal fentanyl alleviates spasticity in the presence of tolerance to intrathecal baclofen. Anesthesiology 1992;76:312-3 14. 12. Lozano AM, Kumar R, Gross RE, et al. Globus pallidus internus pallidotomy for generalized dystonia. Mov Disord 1997; 12365870.

Paraneoplastic “Rubral” Tremor: A Case Report

Paraneoplastic cerebellar degeneration is a complication of malignancies characterized by truncal and appendicular ataxia, dysarthria, and nystagmus. The pathologic hallmark of the dis-

Legends to the Videotape Segment 1: Baseline examination in the intensive-care unit. Segment 2: One hour after a bolus injection of 50 k g ITB. Segment 3: Two weeks after ITB pump insertion (900 pg/ day ITB dosage). Segment 4: Home videotape segment 3 months after discharge from the hospital.

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A videotape accompanies this article. Received July 8, 1997; revision received December 29, 1997. Accepted January 5 , 1998. Address correspondence and reprint requests to Dr. Paola Pergami at the Neurological Department, IRCCS C. Mondino, via Palestro 3, 27100 Pavia, Italy.

CLINICAUSCIENTIFIC NOTES ease is a diffuse and pronounced loss of cerebellar Purkinje cells, together with proliferation of Bergmann astrocytes. Spotty inflammatory lesions may be found. The onset of clinical symptoms may be acute or subacute, and may precede or follow the clinical appearance of malignancy. The syndrome has been reported most frequently with gynecologic cancer and Hodgkin’s lymphoma but may be present with other malignancies, including non-Hodgkin’s lymphoma, and carcinoma of the lung, stomach, colon, and testis.’ High titers of autoantibodies directed against cerebellar Purkinje cells (APCA, previously called anti-Yo) may be detected in the serum and cerebrospinal fluid of patients with the syndrome accompanying breast or gynecologic cancer. However, the pathologic picture and the fully developed clinical syndrome are identical in seronegative and seropositive patients. We report a case of paraneoplastic cerebellar degeneration that featured a “rubral” tremor and an unusual “reset” phenomenon.

Case Report In 1987, a 47-year-old woman was diagnosed as having a peritoneal carcinomatosis resulting from ovarian cancer; she received four cycles of 90 mg/m2 cisplatin- and 900 mg/m” cyclophosphamide-based chemotherapy. In the following years, she underwent recurrent surgical procedures (lymphoadenectomy, adnexectomy, omental resection, removal of a pelvic mass, and lymphoadnexectomy) together with repeated cycles of cisplatin-, cyclophosphamide-, and 110 mgkycle doxorubicin-based chemotherapy. In August 1994, a pelvic CT scan showed a diffuse relapse of the ovarian cancer and she received five cycles of 400 mg/ m2 carboplatin each. After a few months, a subacute cerebellar syndrome appeared with gait and limb ataxia, scanning speech, and nystagmus. Brain MFU was negative. Cerebrospinal fluid examination showed normal protein and glucose values, no cells, and a mild intrathecal immunoglobulin synthesis. Iatrogenic, toxic, and metabolic causes as well as nutritional deficiencies were ruled out. Specific anticerebellar antibodies (APCA) were not found. A therapeutic trial of immunoglobulin (0.4 g k g IVIG for 5 consecutive days) failed. No progression of the neurologic syndrome was noted for a few months when a 3-4 Hz resting tremor on the right side appeared. The tremor worsened with posture and voluntary movements but was abolished by sleep. During the following weeks, the tremor involved the head and trunk and became bilateral. Neurologic examination showed a mild right limb hyposthenia without abnormal muscular tone, alteration of tendon reflexes, or Babinski sign. Evaluation of superficial and deep sensation did not display abnormal findings. Cognition was normal. Contrast brain CT scan and specific antibodies remained negative. Intense manual compression of calf or arm muscles produced prolonged (minutes) arrest of the tremor (see the videotape). We were not able to reproduce this effect with other sensory input (touch, vibration, temperature). The patient was treated with up to 5 mg/day clonazepam and L-dopa with no improvement. Videotaping was performed in this late phase of the disease.

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Discussion Tremor at rest increased by movement is commonly associated with lesions in the midbrain. In 1938, Denny-Brown coined the term “rubral tremor.”’ In 1904, Gordon Holmes fully described the syndrome and hypothesized that damage to the red nucleus was c a ~ s a t i v e The . ~ disorder is a combination of resting, postural, and kinetic tremor. The tremor at rest worsens with posture and movement, and is increased by voluntary movements of the contralateral limb. A characteristic frequency of 2-5 Hz is reported. The pathophysiology of the tremor is still reason for controversy. The role of the red nucleus is conceivable merely as an intermediate station in cerebello-thalamic pathways and rubroolivo-cerebello-rubral 1 0 0 ~ sIn . ~this perspective, the label “rubral” retains a simple historic meaning. Recently, Wills and coworker? proposed that all pathologic tremors are associated with abnormal bilateral cerebellar activation. Our case can be a clinical confirmation of their hypothesis. Because “rubral tremor” is a combination of all kinds of tremors, its association with a cerebellar paraneoplastic degeneration may stress the importance of cerebellum in tremorgenesis. Moreover, the time interval between the onset of her paraneoplastic neurologic syndrome and the development of tremor is classic of rubral tremor which usually appears a few ~ e e k s ~ , ~ after a neurologic insult. The paraneoplastic cerebellar syndrome in this patient is peculiar. Despite the absence of autoantibodies directed against cerebellar Purkinje cells, a paraneoplastic syndrome is suggested by the lack of metastatic cerebellar lesions, nutritional deficiencies, and metabolic or iatrogenic causes (metoclopramide and the antineoplastic drugs used are not known to produce a similar syndrome) for the cerebellar disease. MRI together with cerebrospinal fluid findings excluded a meningeal infiltration. Tremor is not a common finding in paraneoplastic cerebellar degeneration. To our knowledge, this kind of tremor in a paraneoplastic syndrome has been reported only once in association with dystonia and parkins~nism.~ Because in this patient no signs of parkinsonism were present, the case represents the first description of cerebellar degeneration beginning with rubral tremor without accompanying extrapyramidal features. Regarding the remarkable effect of muscular compression on the tremor, we are unable to find a clear explanation. Reset phenomenon is well known in various kinds of tremors but usually lasts for fractions of a second. We suggest that the strong nociceptive and propioceptive peripheral stimulation produced a prolonged inhibition of the cerebellar efferent system to the ventrolateral thalamus or to the thalamic nuclei.

Legends to the Videotape Segment 1: Resting tremor worsens by adopting posture and attempting movement and increases by voluntary movements of contralateral limbs. Segment 2: The vigorous compression of muscles causes a complete and long-lasting arrest of the pathologic movement. Segment 3: Absence of clinical evidence of nuclear or fascicular oculomotor involvement. Acknowledgment: The authors thank Dr. R. Sangermani,

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Pediatric Department, S. Carlo Hospital, Milan, Italy, for technical assistance.

F. Simonetti P. Pergami K. Marinu Aktipi G. Giardini M. Ceroni Neurological Department IRCCS “C. Mondino ’’ Pavia, Italy P. Lattuada G. Valenti Neurologia Ospedale San Carlo Borromeo Milan, Italy

References 1. Posner JB. Neurologic Complications of Cancer. Philadelphia, PA: FA Davis Co, 1995. 2. Denny-Brown D. Rubral tremor. Proceedings of the Royal Society of Medicine 1938;3 1:718-719. 3. Holmes G. On certain tremors in organic cerebral lesions. Brain 1904;27:327-375. 4. Carpenter MB. Functional relationships between the red nucleus and the brachium conjunctivum. Neurology 1957;7:427437. 5. Wills AJ, Thompson PD, Findley LJ, Brooks DJ. A positron emission tomography study of primary orthostatic tremor. Neurology 1996;46:747-752. 6 . Hopfensperger KJ, Busenbark K, Koller WC. Midbrain tremor. In: Findley LJ, Koller WC, eds. Handbook of Tremor Disorders. New York, NY: Marcel Defier Inc, 1995:455459. 7. Golbe LI, Miller DC, Duvoisin RC. Paraneoplastic degeneration of the substantia nigra with dystonia and parkinsonlsm. Mov Disord 1989;4:147-152.

Clozapine Treatment of Delayed-Onset Paroxysmal Hemidystonia

In the majority of cases of hemidystonia, CT or MRI studies reveal lesions of structures within the contralateral hemisphere, generally the caudate nucleus, lentiform nucleus (particularly the putamen), or thalamus.’-3 According to Marsden et al.,” hemidystonia could be the result of delivery of inappropriate commands to the premotor cortex, particularly the supplementary motor area. Lesion-induced dystonic movement disorders of delayed onset have been reported up to 14 years after the original In the interval, these patients demonstrated no or only minimal static neurologic abnormalities. Diagnosis may be difficult, especially if the dystonic movements are of a paroxysmal and intermittent nature. The current therapy of hemi-

A videotape accompanies this article. Received June 4, 1997; revision received October 21, 1997. Accepted October 29, 1997. Address correspondence and reprint requests to Dr. Iris Maurer at the Department of Epileptology, Sigmund-Freud-Str. 25, 53 105 Bonn, Germany.

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dystonia remains highly unsatisfactory and is rarely a complete success.6 We report a patient presenting with epileptic seizures since age 4 and delayed-onset hemidystonia after ipsilateral hemiparesis in whom pharmacotherapy with low-dose clozapine led to the complete disappearance of paroxysmal hemidystonic movements.

Case Report The patient was first seen at age 54 years for paroxysmal abnormal movements of the right side of her body. Birth and earl y-childhood psychomotor development were normal. Since age 4, however, she had experienced episodes of loss of consciousness for a few seconds’ duration which were diagnosed as epileptic seizures and treated with various anticonvulsants. Otherwise she was well until age 10 when right hemiparesis and aphasia developed. Neurosurgery was performed and both the aphasia and the hemiparesis resolved. She was again able to walk and run and did not recall any functional limitations. Paroxysmal involuntary movements started after a delay of 5 years. Approximately 20 to 40 times daily her fingers would extend with flexion of the right wrist and arm, the right leg would be outstretched, and a bowing movement of the trunk with a slight rotation to the left would occur. In some attacks there was also involvement of the left leg. These attacks were brief with a typical duration of less than 1 minute, repetitive, and occurring intermittently every second day. She was always alert during the attacks. At approximately age 20, her right foot, and a few years later her left foot, became progressively plantar flexed with equivarus posturing rendering her wheelchairbound. The paroxysms necessitated a change to writing with her left hand. All these movements disappeared during sleep but tended to be increased with fatigue, stress, and emotional distress. Some of the attacks were precipitated by movements of the affected limbs, but most started spontaneously at rest. They were thought to be epileptic in nature and over a period of years the patient was given multiple trials with adequate doses of anticonvulsants but without improvement. On admission, the disorder was severely disabling, interfering with the activities of daily living. Her medication included carbamazepine, valproic acid, lamotrigine, and diazepam. All laboratory investigations were normal. She was alert and cooperative. The cranial nerves and muscle power were normal. Deep tendon reflexes were more brisk in the right limbs; plantar response could not be obtained because of pes equinovarus. There was no sensory abnormality. Between attacks, there was fixed dystonia of the right foot and, to a lesser extent, of the left foot. Neuropsychologic assessment demonstrated reduced verbal fluency and slow motor performance as signs of possible left frontal impairment. MRI showed cerebellar atrophy but no pathology of the basal ganglia. Although there were multiple clips at the left frontotemporal site of the initial neurosurgical intervention, no structural lesion could be detected. Simultaneous EEG recording and audiovisual monitoring during and between multiple episodes of abnormal movements revealed no corresponding EEG abnormalities. Up to 600 mg tiaprid per day was ineffective. Gradual reduction of the anticonvulsants induced the occurrence of tonicclonic seizure associated with typical post-ictal EEG changes and a rise in prolactin levels. Anticonvulsants were continued and no further epileptic seizures occurred. Therapy with up to