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Isolated Frontal Disequilibrium as Presenting Form of Anti-Hu Paraneoplastic Encephalomyelitis Yaroslau Compta, MD,1 Francesc Valldeoriola, MD, PhD,1* Xabier Urra, MD,1 Beatriz Go´mez-Anso´n, MD, PhD,2 Lorena Rami, PhD,1 Eduardo Tolosa, MD, FRCP,1 and Francesc Graus, MD, PhD1 1 Department of Neurology, Institute of Neurosciences, Hospital Clı´nic i Universitari de Barcelona, Barcelona, Catalonia, Spain; 2Department of Radiology, Diagnostic Imaging Center, Hospital Clı´nic i Universitari de Barcelona, Barcelona, Catalonia, Spain
Abstract: Anti-Hu encephalomyelitis is one of the most frequent paraneoplastic syndromes, classically presenting with diffuse neurological involvement. We report a 69-year-old man presenting with a three-month isolated, progressive gait disorder with normal neurological examination, except for loss of balance and gait failure reminding frontal disequilibrium, only accompanied by a very mild rigidity of his right foot. MRI of the brain showed hyperintensities in both amygdale and left putamen. EMG study showed no abnormal continuous spontaneous fiber activity. Because of fast progression and MRI findings, anti-Hu antibodies were tested, resulting positive. Mediastinal biopsy of two adenopathies detected by body-PET, confirmed an oat-cell carcinoma. The patient received oral steroids and oncological therapy. One year later, the tumor is in remission. His gait and abnormal posture of right leg are normal. Only mild residual hyperintensities persist on follow-up MRI. A paraneoplastic syndrome should be considered in the differential diagnosis of subacute, fast progressive gait disorders. © 2007 Movement Disorder Society Key words: gait failure; frontal disequilibrium; anti-Hu antibodies; paraneoplastic encephalomyelitis.
Paraneoplastic encephalomyelitis (PEM) is a multifocal inflammatory disorder of the central nervous system (CNS) associated with remote cancer.1 Neurological dysfunction is assumed to arise from an autoimmune reac-
This article includes supplementary video clips, available online at http://www.interscience.wiley.com/jpages/0885-3185/suppmat. *Correspondence to: Francesc Valldeoriola, Department of Neurology, Institut de Neurocie`ncies, Hospital Clı´nic i Universitari de Barcelona, C/ Villarroel, 170, 08036-Barcelona, Catalonia, Spain. E-mail:
[email protected] Received 15 November 2006; Revised 15 November 2006; Accepted 19 November 2006 Published online 31 January 2007 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21371
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tion directed against onconeuronal antigens present in both tumor tissue and human nervous system. Anti-Hu antibodies2 are the most prevalent, although several other circulating autoantibodies have been identified. Diverse malignancies have been reported in PEM, small-cell lung carcinoma (SCLC) being the most frequent associated neoplasm. Neurological manifestations commonly precede the diagnosis of the tumor and the neurological dysfunction may be more incapacitating than the one produced by the associated cancer. Anti-Hu-associated encephalomyelitis usually presents with multifocal involvement of both peripheral (mixed sensory-motor neuropathy, dysautonomia) and central nervous system (neuropsychiatric symptoms, seizures, cranial nerve palsies, cerebellar signs).3,4 Isolated presentations other than limbic encephalitis or pure sensory neuronopathy are very uncommon. To date, isolated gait and balance disturbance as a presenting form of anti-Hu syndrome has not been reported in the literature. We herein describe a patient presenting with isolated acute disequilibrium that led to the diagnosis of anti-Hu-associated PEM followed by complete neurological recovery after specific treatment of the tumor and symptomatic treatment with oral steroids. CASE REPORT A 69-year-old man presented a 3-month history of progressive gait and balance disturbances. Falls became frequent in a few weeks after the onset of symptoms and, subsequently, unassisted walking and even standing became impossible. The patient had no further complaints. Relatives commented that the patient presented a very mild forgetfulness in the previous weeks. On admission, the patient scored 26 in the MMSE with mistakes in recent memory. Cranial nerves, strength, and sensory examination were well preserved. There were no parkinsonian signs, except for mild rigidity in right lower limb. The right foot showed a tendency to adduction at rest and when walking. Limb ataxia or other signs of cerebellar dysfunction were absent. Deep tendon reflexes were normal, and there were no signs of pyramidal release. Balance was very poor: he was unable to stand unsupported, falling backwards when left alone. He could walk helped by a person and a crutch with a short-stepped and slightly wide-based gait. There was neither shuffling nor freezing. The gait pattern was dominated by impaired balance and the inability to organize trunk and leg movements, suggesting a frontal disequilibrium (Video Segment 1). Laboratory tests disclosed no abnormalities and chest X ray was normal. Brain MRI showed no vascular lesions or ventricular enlargement. Both amygdalar regions (Fig. 1a)
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apy. Balance and gait improved in a few weeks. At 9 months follow-up, the tumor was in complete remission. Postural imbalance and gait had become normal, as there was no longer abnormal posture of his right leg (Video Segment 2). Neuropsychological testing showed a MMSE score of 29 with return to normality of frontal functions, memory, verbal fluency, and cognitive flexibility scores. Follow-up MRI showed only very mild hyperintensities of the amygdalas and the left putamen. (Fig. 1b,d).
FIG. 1. MRI findings: (a) Initial FLAIR (TI ⫽ 2500; TR ⫽ 9000; TE ⫽ 114; thickness ⫽ 5) axial MR image shows hyperintensities at the level of the medial temporal lobes, mainly involving amygdalas (image suggestive of limbic encephalitis); (b) Follow-up (after 10 months) axial FLAIR (TI ⫽ 2500; TR ⫽ 9000; TE ⫽ 114; thickness ⫽ 5) shows persistent, but less marked hyperintensity of the amygdalas; (c) Initial DWI (TR ⫽ 3500; TE ⫽ 94; b ⫽ 1000; thickness ⫽ 5) axial MR image shows increased signal intensity in the left putamen; (d) Follow-up (after 10 months) DWI (TR ⫽ 3700; TE ⫽ 94; b ⫽ 1000; thickness ⫽ 5) shows persistent hyperintensity in the left putamen.
and the left putamen (Fig. 1c) were mildly hyperintense on both FLAIR and diffusion-weighted MR images (DWI). A comprehensive neuropsychological battery including memory, language, praxis, visuospatial, and frontal functions showed mild verbal long-term memory dysfunction along with frontal functions impairment, including verbal fluency and cognitive flexibility, whereas language, praxis, and visuospatial functions were normal. Nerve conduction studies ruled out the existence of peripheral neuropathy or denervation in lower limb muscles. Neurophysiological studies disclosed no signs of abnormal continuous spontaneous fiber activity and both anti-GAD and antiamphiphysin antibodies resulted negative. According to the fast evolution of the symptoms and the amygdalar hyperintensities observed on MRI (suggestive of limbic encephalitis), antionconeuronal antibodies were also investigated, and anti-Hu IgG antibodies were detected. Subsequent body-PET scan using 18Fglucose identified two mediastinal adenopathies, whereas 18 F-glucose PET imaging of the brain did not disclose any hypometabolical area. Pathological examination of adenopathies via mediastinoscopy confirmed SCLC. A diagnosis of definite anti-Hu paraneoplastic syndrome was given, and the patient was started on oral steroids 1 mg/kg/day followed by chest radiotherapy and chemother-
DISCUSSION To our knowledge, isolated balance and gait disturbance as a presenting form of anti-Hu syndrome has not been previously reported in the literature. This case illustrates an uncommon presentation of PEM associated to anti-Hu antibodies (as diagnosed using recently proposed diagnostic criteria4). Anti-Hu-associated PEM usually presents with diffuse central nervous system involvement or with five classical and specific syndromes3: sensory neuronopathy, mixed but predominantly motor neuropathy, limbic encephalitis, brainstem or cerebellar encephalitis, and dysautonomy. Nevertheless, these syndromes tend to present in combination, with one or other being the predominant feature, depending on the case.3 Only limbic encephalitis and sensory neuronopathy constitute relatively frequent isolated presentations. Gait dysfunction and disequilibrium may appear in PEM as an expression of the deficit of diverse neural structures. In the case presented here, the complaints of our patient related to the balance and gait disorder were the dominating symptom at disease presentation. Balance and gait disorders constitute a controversial issue and several classifications have been published with little consensus. One of the most widely used classifications,5 divided gait disorders into lower, middle, and higher level gait disturbances. The latter group has been considered to account for the majority of cases related to vascular pathology5 and neurodegenerative diseases, including advanced Parkinson disease and the majority of atypical Parkinsonisms.5 Our patient afforded the elements defining his balance and gait pattern as a frontal disequilibrium, showing inability to organize trunk and leg movements to rise, leading the patient to lean back when trying to get up from a chair, making it impossible to stand unsupported. According to the aforementioned classification, this would imply dysfunction of fronto-subcortical (mainly fronto-basal) pathways in our patient. However, detailed neurological examination disclosed slight right leg stiffness and a very mild inverted posture of right foot, thorough neuropsychological testing revealed mild cognitive deficits, and MRI featured signs of basal ganglia and amygdalar involvement. Hence, an anatomic basis for the balance and gait disturbance in
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this patient could be understood with the supposition of a more widespread disease than the initial clinical expression suggested, such as a diffuse encephalomyelitis with predominant frontal-subcortical and limbic involvement. Another possible explanation accounting for the gait dysfunction of our patient would be that of a very selective brainstem involvement, including areas near to the pedunculo-pontine nucleus (PPN), which has been implicated in gait rhythmicity and generation.6 Such a small area may not be clearly identified on MRI. Acute and subacute balance and gait disturbances are generally thought to be related to diffuse cerebrovascular disease or to focal stroke or hemorrhage within the thalamus, the PPN,7 and the cerebellum.8 Other causes of subacute balance disorders include chronic hydrocephalus of the adult or degenerative diseases like progressive supranuclear palsy.5 Even the focal involvement of stiffleg syndrome or distal dystonia of the foot (it is to be noted that putaminal hyperintensity on MRI was contralateral to the foot showing a tendency to abnormal posturing) can cause a certain degree of postural imbalance.9 In the present case, all these diagnosis were appropriately ruled-out by clinical progression, neurological examination, MRI, and specific laboratory and neurophysiological tests. The dramatic response to combined oncological and immunosuppressive treatment is also noticeable in our case, as the few published studies on this regard (probably limited by the small sample sizes due to the low frequency of PEM) have only shown clear response in isolated cases, failing to demonstrate a significant benefit in statistical analysis.10 We conclude that PEM should be considered in the differential diagnosis of isolated balance and gait disorders with subacute onset and rapid progression, even in the absence of known cancer and other clinical, neurophysiological or neuroimaging supportive evidences. The early diagnosis of PEM may lead to successful oncological and immunosuppressive therapy with subsequent neurological recovery and improvement of the prognosis of associated cancer. LEGENDS TO VIDEOTAPE Segment 1. Loss of balance (falling backwards) and disorganization of trunk and leg movements dominate patient’s gait pattern. The patient needs help of a person and a crutch to walk, with a short-stepped and mildly wide-based gait, as well as a slightly adducted, inverted posture of his right foot. Segment 2. The patient, with his tumor in remission, features normal gait and no abnormal posturing of his right leg.
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REFERENCES 1. Henson RA, Hoffman HL, Urich H. Encephalomyelitis with carcinoma. Brain 1965;88:449-464. 2. Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology 1985; 35:538-543. 3. Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-48. 4. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135-1140. 5. Nutt JG, Marsden CD, Thompson PD. Human walking and higherlevel gait disorders, particularly in the elderly. Neurology 1993; 43:268-279. 6. Bhidayasiri R, Hathout G, Cohen SN, Tourtellotte WW. Midbrain ataxia: possible role of the pedunculopontine nucleus in human locomotion. Cerebrovasc Dis 2003;16:95-96. 7. Masdeu JC, Alampur U, Cavaliere R, Tavoulareas G. Astasia and gait failure with damage of the pontomesencephalic locomotor region. Ann Neurol 1994;35:619-621. 8. Alarcon F, Tolosa E, Munoz E. Focal limb dystonia in a patient with a cerebellar mass. Arch Neurol 2001;58:1125-1127. 9. Saiz A, Graus F, Valldeoriola F, Valls-Sole´ J, Tolosa E. Stiff-leg syndrome: a focal form of stiff-man syndrome. Ann Neurol 1998; 43:400-403. 10. Uchuya M, Graus F, Vega F, Rene R, Delattre JY. Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry 1996;60:388-392.
Cell Type-Specific Neuronal Loss in the Putamen of Patients with Multiple System Atrophy Kenta Sato, MD,1 Ryuji Kaji, MD, PhD,1 Sadayuki Matsumoto, MD, PhD,2 and Satoshi Goto, MD, PhD1* 1
Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima, Japan; 2Department of Neurology, Kitano Hospital and Neurological Center, Osaka, Japan Abstract: Using antibodies to calcineurin (CaN) and choline acetyltransferase (ChAT), we performed topographical and cellular immunohistochemical analysis on the posterior putamen of autopsied patients with multiple system atrophy
*Correspondence to: Dr. Satoshi Goto, Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima 770-8503, Japan. E-mail:
[email protected] Received 30 October 2006; Revised 30 October 2006; Accepted 4 December 2006 Published online 31 January 2007 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21385
