Clinical Neurology and Neurosurgery 106 (2004) 187–196 Sudden onset aphasic hemiplegia: an unusual manifestation of disseminated encephalomyelitis Vesna V. Brinar a,∗ , Charles M. Poser b , Silvije Basic a , Zeljka Petelin a a Department of Neurology, Faculty of Medicine, University of Zagreb, University Hospital Centre Rebro, Kispaticeva 12, 10000 Zagreb, Croatia b Department of Neurology, Harvard Medical School, Boston, MA 02215, USA Abstract The association of the sudden onset of aphasia with hemiplegia, hemisenosry defect, and facial palsy, with MRI evidence of white matter lesions, requires differentiation between multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). We have observed eight patients with such a syndrome, all of whom were originally diagnosed as multiple sclerosis, but who, on closer examination, turned out to be instances of disseminated encephalomyelitis. The patterns of demyelination seen in T2-weighted MRI are quite different in both conditions. In two of our patients, MRI reverted to normal after the treatment; in others, the images remained unchanged. A review of the reported cases of multiple sclerosis presenting with the acute onset of aphasia, reveals that the majority of them are, in reality, instances of acute disseminated encephalomyelitis with a much better prognosis. Most of these cases are monophasic and immunomodulatory treatment is inappropriate. © 2004 Published by Elsevier B.V. Keywords: Aphasic hemiplegia; Acute disseminated encephalomyelitis; Multiple sclerosis; MRI 1. Introduction The sudden development of aphasia and hemiparesis in previously healthy people is most often the consequence of cortical lesions due to occlusion of the middle cerebral artery or its branches [1,2]. Aphasia is classically caused by cortical lesions in the posterior two-thirds of the third frontal convolution [1–5], but subcortical lesions involving the putamen, internal capsule, caudate nucleus, and thalamus are also associated with various forms of aphasia (e.g. motor, transcortical, conduction) [1–6]. Despite the stroke-like onset, the presence of demyelinating lesions leads to the consideration of the diagnosis of multiple sclerosis (MS) in some of these cases, especially when the patient is still relatively young. Aphasia is uncommon in MS, and when it occurs, it is usually seen in patients with massive demyelination, mimicking brain tumor, in cases with severe callosal involvement, or with large bilateral subcortical lesions [3,7–11]. We have observed eight patients with the syndrome of sudden onset aphasic hemiplegia associated with demyeli∗ Corresponding author. Tel.: +385-1-238-8342; fax: +385-1-26-21-546. E-mail addresses: vesna.brinar@htnet.zg, vesna.brinar@zg.tel.hr (V.V. Brinar). 0303-8467/$ – see front matter © 2004 Published by Elsevier B.V. doi:10.1016/j.clineuro.2004.02.015 nating lesions, all of whom were diagnosed as MS. Our review of the published cases of aphasia in MS suggests that in many of those instances, the correct diagnosis is disseminated encephalomyelitis. 2. Case reports 1. A 15-year-old girl had always enjoyed good health except of allergic rhinitis. On 20 November 2002, during a basketball game, she suddenly experienced a rapidly progressive right hemiparesis as well as a speech problem described as an expressive aphasia. These symptoms increased in severity over the next 2 or 3 days, including the development of dyslexia. She was admitted to an outside hospital. At that time, there were 218/3 white blood cells and 36 mg/100 ml of protein, and several oligoclonal bands (OCB) in the CSF. Serological tests for neurotropic viruses were negative. She was treated with 500 mg of i.v. methylprednisolone (IVMP) daily for 3 days and 5 g of immunoglobulin for 5 days without improvement of her condition. She was diagnosed as MS. A month later she was admitted to our service. Spontaneous speech and comprehension of spoken language, repetition, naming ability, reading, and writing were tested, and she was found to have a non-fluent 188 V.V. Brinar et al. / Clinical Neurology and Neurosurgery 106 (2004) 187–196 Fig. 1. Case 1: MRI—March 2003. dysphasia, with writing difficulties due to the right hand paresis. She could read and understand written language. She also had a right homonymous hemianopsia and a spastic right hemiparesis. Visual evoked potentials showed delayed latencies in the right optic nerve. Brain MRI revealed extensive demyelinating lesions of the left hemisphere (Fig. 1), but MRI of the spinal cord was normal. Our diagnosis was acute disseminated encephalomyelitis (ADEM). She was treated for 7 days with 500 mg of IVMP, followed by a tapering course of oral steroids. Her MRI lesions remained the same but there was gradual improvement of her clinical status so that 6 months later, the only residual was a right hyperreflexia, and a year later, she was once again able to play basketball. Her most recent MRI showed marked regression of the area of demyelination (Fig. 2). 2. In 1997, a previously healthy 26-year-old woman suddenly developed right-sided weakness and somnolence, along with motor aphasia and diplopia. MRI of the brain revealed extensive demyelination predominantly in the left hemisphere (Fig. 3). OCB were present in the CSF. She was treated with IVMP which resulted in the disappearance of all her symptoms. She was diagnosed as MS. She has been followed regularly every three to six months and her neurological status has remained unchanged: she has slight spasticity and hyperreflexia of the right extremities. A recent MRI is improved from the one in 1997 (Fig. 3). Our diagnosis is ADEM based on the monophasic nature of the illness and the MR image. 3. A 22-year-old woman with the diagnosis of diabetes mellitus type I from the age of 9, on insulin since the age of 17, developed a diabetic nephropathy and bilateral cataracts. In March 2003, a week after vaccination against influenza, she suddenly developed blurred vision in both eyes and diplopia. Her status deteriorated over the next several days, and she developed sensorimotor Fig. 2. Case 1: MRI—December 2003. V.V. Brinar et al. / Clinical Neurology and Neurosurgery 106 (2004) 187–196 Fig. 3. Case 2: MRIs—1997, 1998, and 1999. aphasia, alexia, apraxia, ataxia, left internuclear ophthalmoplegia, right hemiparesis, and supranuclear facial palsy. She then progressed to tetraparesis. Her dysphagia required gastric tube feeding. An MRI of the brain revealed multiple demyelinating lesions of which the largest ones were situated in the left parietal and the pontomesencephalic regions (Fig. 4). She had OCB in her CSF, but tests for Borrelia and neurotropic viruses were negative. VEP indicated damage in both optic tracts. IVMP therapy was given, followed by i.v. immunoglobulin in a daily dose of 5.0 g for 10 days, along with intensive physiotherapy. After 5 months, there had been significant improvement of her clinical status, with only a discrete right hemiparesis and mild dysarthria persisting, but normal language functions. She is able to walk unaided and has resumed her schooling. A recent MRI shows no change (Fig. 5). The single episode coupled with the extensive demyelination led us to the diagnosis of ADEM. 189 4. In December 2000, a 21-year-old man suddenly developed speech disturbances and incoordination of the right arm. His past medical history included infectious mononucleosis at age 5, frequent sinus infections and a tick bite in 1997. Several MRIs of the brain showed a demyelinating lesion in the left hypothalamus (Fig. 6). A thorough cardiac investigation looking for a source of emboli, including transthoracic and transesophageal echocardiography, was normal. In September 2002, he worsened to a spastic hemiparesis, and had OCB in his CSF. A new brain MRI showed the same lesion in the right crura cerebri (Fig. 7). MR angiography and contrast cerebral angiography ruled out a cerebral vasculitis. Immunological tests for various autoimmune diseases, as well as for Borrelia, were all negative. Clinical improvement followed short-term IVMP therapy. He has been seen every six months, and has remained quite stable showing only slight right-sided weakness and hyperreflexia. Our diagnosis was recurrent DEM. 5. On 18 April 2002, this healthy 26-year-old woman noted a tingling sensation in her right leg; the next morning she suddenly developed weakness of her right extremities and speech impairment. This progressed to complete motor aphasia and right hemiparesis over the next three days. MRI of the brain revealed extensive demyelination in the area of the corpus callosum and basal ganglia (Fig. 8). She was treated with IVMP and physical therapy, with partial recovery. She was diagnosed as MS. In September 2002, she was admitted to our service. A new brain MRI showed the same demyelinating lesions in the periventricular white matter, more on the left, and in the region of the corpus callosum. She was treated again, for 5 days with 1 g of IVMP, followed by tapering oral steroids. As a result both her gait and speech improved. In October 2002, she still had an expressive dysphasia, moderately severe right spastic hemiparesis and hemihypesthesia, a discrete right supranuclear facial and tongue paresis. VEPs indicated damage in both optic tracts. All immunological tests were within normal limits. She was treated again with a combination of immunoglobulin and IVMP; this time with satisfying, gradual clinical improvement, leaving her with a slight gait impairment due to right hemiparesis, and a discrete expressive dysphasia. Our diagnosis is ADEM. 6. An 18-year-old boy developed right retrobulbar neuritis in May 1999. He had been vaccinated against poliomyelitis a few months previously. He was treated with local corticosteroid injections and his sight gradually returned. His brain MRI was normal. Two years later, in 2001, he developed weakness in the right arm and leg without speech disturbance. He was admitted to the children’s hospital where a brain MRI revealed a few periventricular demyelinating lesions as well as a lesion at the medullo–spinal junction (Fig. 9). VEP showed bilaterally delayed latencies and OCB were found in the CSF, but cells and protein content were normal. He 190 V.V. Brinar et al. / Clinical Neurology and Neurosurgery 106 (2004) 187–196 Fig. 4. Case 3: MRI—March 2003. was diagnosed as having MS, and was treated with i.v. immunoglobulins without improvement. He was then admitted to our service, and was treated for 5 days with 500 mg of IVMP, resulting in complete recovery except for the persistence of right-sided paresthesiae for several months. Interferon treatment was Fig. 6. Case 4: MRI—December 2000. Fig. 5. Case 3: MRI—December 2003. Fig. 7. Case 4: MRI—September 2002. V.V. Brinar et al. / Clinical Neurology and Neurosurgery 106 (2004) 187–196 Fig. 8. Case 5: MRI—April 2002. Fig. 9. Case 6: MRI—June 2001 (A). Lesion at medullo–spinal junction (B). 191 192 V.V. Brinar et al. / Clinical Neurology and Neurosurgery 106 (2004) 187–196 Fig. 10. Case 6: MRI—October 2003 (A). Lesion has resolved (B). Fig. 11. Case 7: MRI—April 2003. V.V. Brinar et al. / Clinical Neurology and Neurosurgery 106 (2004) 187–196 intiated at the insistence of his parents based on the previous diagnosis of MS. In September 2002, his clinical status was normal, and a repeat MRI showed regression of the size of the demyelinating lesion. He was seen again in October 2003 193 when he was neurologically normal, as were MRIs of the brain and spinal cord (Fig. 10). The isolated episode, the MRI findings and the lesion’s complete resolution established the diagnosis of ADEM. The interferon therapy was terminated. Fig. 12. Case 7: MRI—January 2004. 194 V.V. Brinar et al. / Clinical Neurology and Neurosurgery 106 (2004) 187–196 Fig. 13. Case 8: MRI—November 2003. 7. A 21-year-old woman suddenly developed weakness and paresthesiae in her right leg and right hand on 16 April 2003. This was associated with a mild headache, a sense of coldness, and slight speech impairment. Brain MRI revealed extensive demyelinating lesions adjacent to the posterior horn of the left lateral ventricle, and in the left temporal and temporo–occipital regions (Fig. 11). No OCB were found in the CSF, and the VEPs were normal. Treatment with IVMP resulted in marked clinical improvement. Six months later, the only abnormality was mild neglect in the right visual field, although, an MRI obtained in January 2004 showed that the lesions remained essentially unchanged (Fig. 12). Our diagnosis was ADEM. 8. A 50-year-old woman with a 3-year history of nonspecific vertiginous episodes, suddenly developed rightsided hemiparesis and sensorimotor aphasia; spontaneous speech was completely absent, as was repetition of spoken words. Brain MRI showed extensive demyelination of both hemispheres more pronounced on the left (Fig. 13). The CSF had OCB but cells and protein level were normal. VEP showed delayed latencies in the right visual pathway. The diagnosis of Schilder’s disease was entertained, and adrenoleukodystrohy and granulomatous infections, such as sarcoidosis and tuberculosis, were excluded by appropriate tests. She did not respond to corticosteroids, but speech fluency and comprehension were much better following i.v. immunoglobulin. Our diagnosis was ADEM. 3. Discussion Large published reviews of MS symptoms record aphasia to be absent or very rare [12,13]. Aphasic problems would not be expected from the typical periventricular demyelinations of MS [13,14], although some authors have noted that the incidence of aphasia in the disease ranges between 1 and 3% [3,14]. The rare cortical plaques of MS can result in aphasia [7,13,15,16], and it can also be caused by extension into cortex of confluent lesions at the gray–white matter junction [12]. Even in those cases, aphasia is rarely the first symptom, and its association with other typical signs of large hemisphere involvement, such as supranuclear facial palsy, hemiparesis, and hemisensory deficit, is most unusual. The majority of MS patients presenting with aphasia are found to have very large areas of demyelination [7–11,15,17,18], or tumor-like plaques [19–30] on MRI, lesions which are most atypical for MS. By contrast, in our eight cases, the large areas of increased signal intensity (AISI) on T-2 weighted MRI are characteristic of DEM. The clinical manifestations, which occur either suddenly or gradually over several days, consist of aphasia and signs of hemispheric involvement, a syndrome that has been described by a number of authors, but most often ascribed to MS [21–32]. Close examination of the clinical and neuroradiological features of these cases make it abundantly clear that they are quite similar to our cases and in fact, instances of DEM [21,23–25]. The fact that complete remission may V.V. Brinar et al. / Clinical Neurology and Neurosurgery 106 (2004) 187–196 occur in such cases is also an important point in favor of DEM [7,8,10]. In most patients who are aphasic as a result of MS or DEM, the AISIs involve the subcortical white matter [21,33,34]. One explanation for this is based on the concept of diaschisis [35,36]. According to this concept, impaired function occurs in one area secondary to an acute focal lesion in a more distant part of the brain; thus, lesions of white matter tracts that are anatomically connected to the cortical language centers produce aphasias or similar speech difficulties which are undistinguishable from those of cortical origin. It is most likely that diaschisis is indeed the basis for the aphasic problems of our patients. Another possible mechanism is a neglect or disconnection syndrome, as exemplified by our Case 8. Her MRI showed large AISIs that involved the whole left frontotemporal region as well as the greater part of the right hemisphere (Fig. 13). She had global aphasia without spontaneous speech and with disturbances of comprehension, and was unable to read and write. In this case, disconnection of brain regions controlling language might be the basis for her aphasia, as is seen in patients with large callosal lesions [19,37,38]. 4. Conclusion Aphasia is extremely rare in MS, but does occur in some cases of cortical demyelination [7] or with large confluent lesions [13,15]. The majority of published reports of MS with aphasia are more likely to be of monophasic or recurrent DEM, characterized by the presence of large AISIs on T-2 weigthed brain MRIs. 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