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Encephalopathy associated with Hashimoto's thyroiditis: an additional case
European Journal of Internal Medicine 14 (2003) 434 – 437 www.elsevier.com/locate/ejim
Brief report
Encephalopathy associated with Hashimoto’s thyroiditis: an additional case M. Bertoni a,*, M. Falcini b, S. Sestini c, L. Niccoli a, C. Nannini a, F. Cantini a a
Divisione di Medicina Interna, Ospedale di Prato, Piazza Ospedale 1, Prato I-59100, Italy b Divisione di Neurologia, Ospedale di Prato, Italy c Divisione di Medicina Nucleare, Ospedale di Prato, Italy Received 18 March 2003; accepted 19 June 2003
Abstract A 35-year-old female with a history of Hashimoto’s thyroiditis (HT) presented with episodic dysphasia and a burst of axial jerks with abdominal muscle contraction and asymmetric blepharospasm as manifestations of encephalopathy associated with HT. Brain magnetic resonance imaging (MRI) showed scattered supratentorial white matter hyperintense T2 foci. Brain single photon emission computerized tomography (SPECT) demonstrated a cortical hypoperfusion in the upper frontal and parietal areas. Corticosteroid therapy induced a rapid improvement of the clinical picture. D 2003 Elsevier B.V. All rights reserved. Keywords: Brain magnetic resonance imaging (MRI); Brain single photon emission computerized tomography (SPECT); Acetazolamide (ACZ) test; Regional cerebral blood flow (rCBF)
1. Introduction Encephalopathy associated with Hashimoto’s thyroiditis (HT) is a rare syndrome of persistent or fluctuating neurological and neuropsychiatric findings that has been described since the second half of the 1960s [1]. In this regard, subacute cognitive impairment, movement disorders, generalized seizures and/or such focal neurological symptoms as stroke-like episodes and monolateral weakness, characterized by a dramatic response to corticosteroids, have been reported [2 – 5]. We describe an additional patient who consecutively developed Raynaud’s phenomenon, HT, and a proteiform neurological picture.
2. Case report A 35-year-old female presented with a 4-year history of episodic dysphasia and a burst of axial jerks with abdominal muscle contraction, asymmetric blepharospasm, as well as thigh and arm spasms elicited in response to Mingazzini’s * Corresponding author. E-mail address: [email protected] (M. Bertoni). 0953-6205/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2003.06.002
posture, sphygmomanometer inflation or simple tactile pressure. In addition, a writing dystonic posture with micrography and a worsening of gait with a tremulous stiffness of glutei were noticed. At the age of 16, Raynaud phenomenon was noticed. At 30, the presence of high levels of thyroid stimulating hormone [TSH; 8.1 mU/l; normal range (n.r.) 0.1– 4 mU/l], normal levels of both fT4 and fT3, as well as high titers of both anti-thyroperoxidase (anti-TPO) antibodies (448 U/ml; n.r. 0 – 35 U/ml) and anti-thyroglobulin (anti-TG) antibodies (1184 U/ml; n.r. 0 –35 U/ml) suggested the diagnosis of HT. Thyroxine replacement was started at a daily oral dosage of 75 Ag. At 31, the patient gradually developed right hand postural tremor, dizziness, weakness in sustained activity and talking, and weakness and stiffness of the right leg. An initial course of oral prednisone 0.5 mg/kg/day induced an incomplete response. At 32, a worsening of weakness, dysphasia and gait led to a new, partially efficacious treatment with prednisone. Physical and neurological examinations disclosed livedo reticularis of the lower limbs, weakness and stiffness of the right leg, and bilateral hypopallesthesia and dysesthesia of the legs. Otologic examination and funduscopy ruled out acoustic and retinal ischemic changes.
M. Bertoni et al. / European Journal of Internal Medicine 14 (2003) 434–437
Laboratory evaluation still showed elevated levels of TSH (6.4 mU/l) and anti-TG antibodies (296 U/ml) with normal fT3, fT4 and anti-TPO antibody levels, while there was no abnormality in routine hematological, biochemical, immunological and neoplastic markers. Cerebrospinal fluid (CSF) analysis revealed a slight increase in protein concentration (54 mg/dl; n.r. < 40 mg/ dl), without either cells or oligoclonal bands. Upper limb digital flow studies displayed vasomotorial alterations consistent with Raynaud’s phenomenon. Electroencephalogram (EEG) showed a slight slowing of posterior activity (9 Hz) and electromyography was normal, with a negative ischemic test. The latency of both acoustic and visual evoked potentials was within the normal range. Somatosensory evoked potentials registered a bilateral alteration of N20 and P40 cortical waves with normal medullar conduction as far as the C7 cervical level. Spinal magnetic resonance imaging (MRI) was normal, while repeated contrast brain MRI showed a stable picture of scattered supratentorial white matter hyperintense T2
Fig. 1. Brain MRI with gadolinium. The flair sequence shows two small, paratrigonal hyperintense foci, without gadolinium enhancement.
435
foci, predominantly in the left paratrigonal area, without blood –brain barrier breakdown (Fig. 1). Three series of consecutive brain perfusion single photon computed emission tomography (SPECT) were performed, the first and second in the baseline condition (T0 and T1), while the third one (T2) was with an acetazolamide (ACZ)mediated cerebral vasodilatation test. The SPECT scans at T0 and T1 showed a regional cerebral blood flow (rCBF) decrease in the left inferior parietal cortex. After ACZ administration, there was a rCBF increase in the left inferior parietal cortex and a remarkable rCBF decrease in the bilateral superior fronto-parietal cortices (Fig. 2). A diagnosis of encephalopathy associated with HT was made and the patient, who was still taking thyroxine replacement at a daily oral dosage of 50 Ag, was also given oral prednisone 1 mg/kg/day, with a dramatic remission of symptoms at 1- and 2-month follow-up visits.
3. Discussion Encephalopathy associated with HT is a syndrome of persistent or relapsing-remitting neurological and neuropsychiatric symptoms, even though thyroid hormone levels are usually within the normal range [2,4,6]. Since the first description by Brain et al. [1], the number of case reports of this syndrome has been progressively increasing, particularly in the last few years. Via a MEDLINE review of the literature, we found 78 references, mostly single case reports and a few small clinical series (118 cases in all, 18 of them in children) [2 –4,6 – 8]. As in previous reports, it was not easy for us to establish the diagnosis of encephalopathy associated with HT in the absence of specific clinical, laboratory or neuroimaging findings. It was, therefore, necessary to exclude all infectious, metabolic, toxic, neoplastic, vascular and paraneoplastic etiologies. The differential diagnosis with other distinct neurological diseases, particularly multiple sclerosis, Creutzfeldt-Jacob disease, Sneddon’s syndrome, Susac’s syndrome and myasthenia gravis, was carefully taken into account, but the neurological features, along with the laboratory and instrumental examinations, enabled us to rule out such diagnoses. Moreover, our patient met the recently suggested criteria for this diagnosis, which encompass a relapsing course, abnormal thyroid function studies, antithyroid antibodies, non-specific EEG alterations, an increased protein concentration in the CSF and, finally, nonspecific white matter changes seen on neuroimaging [6]. The pathogenesis of encephalopathy associated with HT is still controversial. However, the possibility of an autoimmune mechanism being responsible for cerebral vasculitic lesions potentially supporting multifocal alterations of cerebral perfusion or metabolism has been suggested [4,5,9,10]. According to other case reports of encephalopathy associated with HT [11,12], a clear cortical hypoperfusion in brain SPECT was also identified in our patient. Interestingly, with
436
M. Bertoni et al. / European Journal of Internal Medicine 14 (2003) 434–437
Fig. 2. Bilateral decrease in rBCF in the superior fronto-parietal cortices (A) and increase in rBCF in the left inferior parietal cortex (B) after acetazolamide administration (T2) in comparison with the baseline conditions at T0 and T1, respectively. These findings indicate a reduced cerebrovascular reserve with differentiation phenomena in the brain.
M. Bertoni et al. / European Journal of Internal Medicine 14 (2003) 434–437
reference to baseline perfusion defects, the use of an ACZ test disclosed a reduction in rCBF in the upper frontal and parietal areas, consistent with an organic vascular insufficiency [13]. The latter could presumably be supported by the presence of vasculitic lesions of cerebral vessels [13]. Accordingly, data supporting the vasculitic pathogenesis of encephalopathy associated with HT have been provided by the demonstration of T lymphocyte infiltrates of leptomeningeal venules, both in the brain stem of an autopsy subject with longstanding HT and typical features of such a syndrome [14] and in the stereotaxic brain biopsy of another case of encephalopathy associated with HT [15]. Another interesting finding provided by brain SPECT with an ACZ test was the contemporary increase in rCBF in the left parietal cortex, compatible with the presence of still alive but functionally deafferentated cortical neurons, which topographically correlated with white matter MRI sufferance. Finally, in keeping with the great majority of previously reported cases of encephalopathy associated with HT, steroid treatment induced a dramatic improvement of the neurological picture in our patient.
References [1] Brain R, Jellineck EH, Ball K. Hashimoto’s disease and encephalopathy. Lancet 1966;ii:912 – 4. [2] Shaw PJ, Walls TJ, Newman PK, Cleland PG, Cartlidge NE. Hashimoto’s encephalopathy: a steroid-responsive disorder associated with high anti-thyroid antibody titers-report of 5 cases. Neurology 1991; 41:228 – 33. [3] Henchey R, Cibula J, Helveston W, Malone J, Gilmore RL. Electroencephalographic findings in Hashimoto’s encephalopathy. Neurology 1995;45:977 – 81.
437
[4] Kothbauer-Margreiter I, Sturzenegger M, Komor J, Baumgartner R, Hess CW. Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment. J Neurol 1996;243:585 – 93. [5] Canton A, de Fabregas O, Tintore M, Mesa J, Codina A, Simo R. Encephalopathy associated to autoimmune thyroid disease: a more appropriate term for an underestimated condition? J Neurol Sci 2000;176:65 – 9. [6] Sawka AM, Fatourechi V, Boeve BF, Mokri B. Rarity of encephalopathy associated with autoimmune thyroiditis: a case series from Mayo Clinic from 1950 to 1996. Thyroid 2002;12:393 – 8. [7] Henderson LM, Behan PO, Aarli J, Hadley D, Draper IT. Hashimoto’s encephalopathy: a new neuroimmunological syndrome. Ann Neurol 1987;22:140 – 1. [8] Seipelt M, Zerr I, Nau B, et al. Hashimoto’s encephalitis as a differential diagnosis of Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 1999;66:172 – 6. [9] Ghika-Schmid F, Ghika J, Regli F, et al. Hashimoto’s myoclonic encephalopathy: an underdiagnosed treatable condition? Mov Disord 1996;11:555 – 62. [10] Barker R, Zajicek J, Wilkinson I. Thyrotoxic Hashimoto’s encephalopathy. J Neurol Neurosurg Psychiatry 1996;60:234. [11] Forchetti CM, Katsamakis G, Garron DC. Autoimmune thyroiditis and a rapidly progressive dementia: global hypoperfusion on SPECT scanning suggests a possible mechanism. Neurology 1997;49:623 – 36. [12] v. Maydell B, Kopp M, v. Komorowski G, Joe A, Juengling FD, Korinthenberg R. Hashimoto encephalopathy-is it underdiagnosed in pediatric patients? Neuropediatrics 2002;33:86 – 9. [13] Pupi A, Sestini S, De Cristofaro MT, et al. Use of technetium-99m hexamethylpropylene amine oxime SPET for the study of cerebral blood flow reactivity after acetazolamide infusion in patients with Behcßet disease. Eur J Nucl Med 2000;27:700 – 6. [14] Nolte KW, Unbehaun A, Sieker H, Kloss TM, Paulus W. Hashimoto encephalopathy: a brainstem vasculitis? Neurology 2000;54:769 – 70. [15] Shibata N, Yamamoto Y, Sunami N, Suga M, Yamashita Y. Isolated angiitis of the CNS associated with Hashimoto’s disease. Rinsho Shinkeigaku 1992;32:191 – 8.
Brief report
Encephalopathy associated with Hashimoto’s thyroiditis: an additional case M. Bertoni a,*, M. Falcini b, S. Sestini c, L. Niccoli a, C. Nannini a, F. Cantini a a
Divisione di Medicina Interna, Ospedale di Prato, Piazza Ospedale 1, Prato I-59100, Italy b Divisione di Neurologia, Ospedale di Prato, Italy c Divisione di Medicina Nucleare, Ospedale di Prato, Italy Received 18 March 2003; accepted 19 June 2003
Abstract A 35-year-old female with a history of Hashimoto’s thyroiditis (HT) presented with episodic dysphasia and a burst of axial jerks with abdominal muscle contraction and asymmetric blepharospasm as manifestations of encephalopathy associated with HT. Brain magnetic resonance imaging (MRI) showed scattered supratentorial white matter hyperintense T2 foci. Brain single photon emission computerized tomography (SPECT) demonstrated a cortical hypoperfusion in the upper frontal and parietal areas. Corticosteroid therapy induced a rapid improvement of the clinical picture. D 2003 Elsevier B.V. All rights reserved. Keywords: Brain magnetic resonance imaging (MRI); Brain single photon emission computerized tomography (SPECT); Acetazolamide (ACZ) test; Regional cerebral blood flow (rCBF)
1. Introduction Encephalopathy associated with Hashimoto’s thyroiditis (HT) is a rare syndrome of persistent or fluctuating neurological and neuropsychiatric findings that has been described since the second half of the 1960s [1]. In this regard, subacute cognitive impairment, movement disorders, generalized seizures and/or such focal neurological symptoms as stroke-like episodes and monolateral weakness, characterized by a dramatic response to corticosteroids, have been reported [2 – 5]. We describe an additional patient who consecutively developed Raynaud’s phenomenon, HT, and a proteiform neurological picture.
2. Case report A 35-year-old female presented with a 4-year history of episodic dysphasia and a burst of axial jerks with abdominal muscle contraction, asymmetric blepharospasm, as well as thigh and arm spasms elicited in response to Mingazzini’s * Corresponding author. E-mail address: [email protected] (M. Bertoni). 0953-6205/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2003.06.002
posture, sphygmomanometer inflation or simple tactile pressure. In addition, a writing dystonic posture with micrography and a worsening of gait with a tremulous stiffness of glutei were noticed. At the age of 16, Raynaud phenomenon was noticed. At 30, the presence of high levels of thyroid stimulating hormone [TSH; 8.1 mU/l; normal range (n.r.) 0.1– 4 mU/l], normal levels of both fT4 and fT3, as well as high titers of both anti-thyroperoxidase (anti-TPO) antibodies (448 U/ml; n.r. 0 – 35 U/ml) and anti-thyroglobulin (anti-TG) antibodies (1184 U/ml; n.r. 0 –35 U/ml) suggested the diagnosis of HT. Thyroxine replacement was started at a daily oral dosage of 75 Ag. At 31, the patient gradually developed right hand postural tremor, dizziness, weakness in sustained activity and talking, and weakness and stiffness of the right leg. An initial course of oral prednisone 0.5 mg/kg/day induced an incomplete response. At 32, a worsening of weakness, dysphasia and gait led to a new, partially efficacious treatment with prednisone. Physical and neurological examinations disclosed livedo reticularis of the lower limbs, weakness and stiffness of the right leg, and bilateral hypopallesthesia and dysesthesia of the legs. Otologic examination and funduscopy ruled out acoustic and retinal ischemic changes.
M. Bertoni et al. / European Journal of Internal Medicine 14 (2003) 434–437
Laboratory evaluation still showed elevated levels of TSH (6.4 mU/l) and anti-TG antibodies (296 U/ml) with normal fT3, fT4 and anti-TPO antibody levels, while there was no abnormality in routine hematological, biochemical, immunological and neoplastic markers. Cerebrospinal fluid (CSF) analysis revealed a slight increase in protein concentration (54 mg/dl; n.r. < 40 mg/ dl), without either cells or oligoclonal bands. Upper limb digital flow studies displayed vasomotorial alterations consistent with Raynaud’s phenomenon. Electroencephalogram (EEG) showed a slight slowing of posterior activity (9 Hz) and electromyography was normal, with a negative ischemic test. The latency of both acoustic and visual evoked potentials was within the normal range. Somatosensory evoked potentials registered a bilateral alteration of N20 and P40 cortical waves with normal medullar conduction as far as the C7 cervical level. Spinal magnetic resonance imaging (MRI) was normal, while repeated contrast brain MRI showed a stable picture of scattered supratentorial white matter hyperintense T2
Fig. 1. Brain MRI with gadolinium. The flair sequence shows two small, paratrigonal hyperintense foci, without gadolinium enhancement.
435
foci, predominantly in the left paratrigonal area, without blood –brain barrier breakdown (Fig. 1). Three series of consecutive brain perfusion single photon computed emission tomography (SPECT) were performed, the first and second in the baseline condition (T0 and T1), while the third one (T2) was with an acetazolamide (ACZ)mediated cerebral vasodilatation test. The SPECT scans at T0 and T1 showed a regional cerebral blood flow (rCBF) decrease in the left inferior parietal cortex. After ACZ administration, there was a rCBF increase in the left inferior parietal cortex and a remarkable rCBF decrease in the bilateral superior fronto-parietal cortices (Fig. 2). A diagnosis of encephalopathy associated with HT was made and the patient, who was still taking thyroxine replacement at a daily oral dosage of 50 Ag, was also given oral prednisone 1 mg/kg/day, with a dramatic remission of symptoms at 1- and 2-month follow-up visits.
3. Discussion Encephalopathy associated with HT is a syndrome of persistent or relapsing-remitting neurological and neuropsychiatric symptoms, even though thyroid hormone levels are usually within the normal range [2,4,6]. Since the first description by Brain et al. [1], the number of case reports of this syndrome has been progressively increasing, particularly in the last few years. Via a MEDLINE review of the literature, we found 78 references, mostly single case reports and a few small clinical series (118 cases in all, 18 of them in children) [2 –4,6 – 8]. As in previous reports, it was not easy for us to establish the diagnosis of encephalopathy associated with HT in the absence of specific clinical, laboratory or neuroimaging findings. It was, therefore, necessary to exclude all infectious, metabolic, toxic, neoplastic, vascular and paraneoplastic etiologies. The differential diagnosis with other distinct neurological diseases, particularly multiple sclerosis, Creutzfeldt-Jacob disease, Sneddon’s syndrome, Susac’s syndrome and myasthenia gravis, was carefully taken into account, but the neurological features, along with the laboratory and instrumental examinations, enabled us to rule out such diagnoses. Moreover, our patient met the recently suggested criteria for this diagnosis, which encompass a relapsing course, abnormal thyroid function studies, antithyroid antibodies, non-specific EEG alterations, an increased protein concentration in the CSF and, finally, nonspecific white matter changes seen on neuroimaging [6]. The pathogenesis of encephalopathy associated with HT is still controversial. However, the possibility of an autoimmune mechanism being responsible for cerebral vasculitic lesions potentially supporting multifocal alterations of cerebral perfusion or metabolism has been suggested [4,5,9,10]. According to other case reports of encephalopathy associated with HT [11,12], a clear cortical hypoperfusion in brain SPECT was also identified in our patient. Interestingly, with
436
M. Bertoni et al. / European Journal of Internal Medicine 14 (2003) 434–437
Fig. 2. Bilateral decrease in rBCF in the superior fronto-parietal cortices (A) and increase in rBCF in the left inferior parietal cortex (B) after acetazolamide administration (T2) in comparison with the baseline conditions at T0 and T1, respectively. These findings indicate a reduced cerebrovascular reserve with differentiation phenomena in the brain.
M. Bertoni et al. / European Journal of Internal Medicine 14 (2003) 434–437
reference to baseline perfusion defects, the use of an ACZ test disclosed a reduction in rCBF in the upper frontal and parietal areas, consistent with an organic vascular insufficiency [13]. The latter could presumably be supported by the presence of vasculitic lesions of cerebral vessels [13]. Accordingly, data supporting the vasculitic pathogenesis of encephalopathy associated with HT have been provided by the demonstration of T lymphocyte infiltrates of leptomeningeal venules, both in the brain stem of an autopsy subject with longstanding HT and typical features of such a syndrome [14] and in the stereotaxic brain biopsy of another case of encephalopathy associated with HT [15]. Another interesting finding provided by brain SPECT with an ACZ test was the contemporary increase in rCBF in the left parietal cortex, compatible with the presence of still alive but functionally deafferentated cortical neurons, which topographically correlated with white matter MRI sufferance. Finally, in keeping with the great majority of previously reported cases of encephalopathy associated with HT, steroid treatment induced a dramatic improvement of the neurological picture in our patient.
References [1] Brain R, Jellineck EH, Ball K. Hashimoto’s disease and encephalopathy. Lancet 1966;ii:912 – 4. [2] Shaw PJ, Walls TJ, Newman PK, Cleland PG, Cartlidge NE. Hashimoto’s encephalopathy: a steroid-responsive disorder associated with high anti-thyroid antibody titers-report of 5 cases. Neurology 1991; 41:228 – 33. [3] Henchey R, Cibula J, Helveston W, Malone J, Gilmore RL. Electroencephalographic findings in Hashimoto’s encephalopathy. Neurology 1995;45:977 – 81.
437
[4] Kothbauer-Margreiter I, Sturzenegger M, Komor J, Baumgartner R, Hess CW. Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment. J Neurol 1996;243:585 – 93. [5] Canton A, de Fabregas O, Tintore M, Mesa J, Codina A, Simo R. Encephalopathy associated to autoimmune thyroid disease: a more appropriate term for an underestimated condition? J Neurol Sci 2000;176:65 – 9. [6] Sawka AM, Fatourechi V, Boeve BF, Mokri B. Rarity of encephalopathy associated with autoimmune thyroiditis: a case series from Mayo Clinic from 1950 to 1996. Thyroid 2002;12:393 – 8. [7] Henderson LM, Behan PO, Aarli J, Hadley D, Draper IT. Hashimoto’s encephalopathy: a new neuroimmunological syndrome. Ann Neurol 1987;22:140 – 1. [8] Seipelt M, Zerr I, Nau B, et al. Hashimoto’s encephalitis as a differential diagnosis of Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 1999;66:172 – 6. [9] Ghika-Schmid F, Ghika J, Regli F, et al. Hashimoto’s myoclonic encephalopathy: an underdiagnosed treatable condition? Mov Disord 1996;11:555 – 62. [10] Barker R, Zajicek J, Wilkinson I. Thyrotoxic Hashimoto’s encephalopathy. J Neurol Neurosurg Psychiatry 1996;60:234. [11] Forchetti CM, Katsamakis G, Garron DC. Autoimmune thyroiditis and a rapidly progressive dementia: global hypoperfusion on SPECT scanning suggests a possible mechanism. Neurology 1997;49:623 – 36. [12] v. Maydell B, Kopp M, v. Komorowski G, Joe A, Juengling FD, Korinthenberg R. Hashimoto encephalopathy-is it underdiagnosed in pediatric patients? Neuropediatrics 2002;33:86 – 9. [13] Pupi A, Sestini S, De Cristofaro MT, et al. Use of technetium-99m hexamethylpropylene amine oxime SPET for the study of cerebral blood flow reactivity after acetazolamide infusion in patients with Behcßet disease. Eur J Nucl Med 2000;27:700 – 6. [14] Nolte KW, Unbehaun A, Sieker H, Kloss TM, Paulus W. Hashimoto encephalopathy: a brainstem vasculitis? Neurology 2000;54:769 – 70. [15] Shibata N, Yamamoto Y, Sunami N, Suga M, Yamashita Y. Isolated angiitis of the CNS associated with Hashimoto’s disease. Rinsho Shinkeigaku 1992;32:191 – 8.