Acta Neurol Belg DOI 10.1007/s13760-015-0451-y
LETTER TO THE EDITOR
Febrile Hashimoto’s encephalopathy associated with Hashitoxicosis Tingting Lu • Zhiming Zhou • Aimin Wu Bing Qin • Zhengqi Lu
•
Received: 19 January 2015 / Accepted: 24 February 2015 Ó Belgian Neurological Society 2015
Introduction Hashimoto’s encephalopathy (HE) is a rare autoimmune disease characterized by encephalopathy and high titers of antithyroid antibodies [1]. Fever was rarely noticed. Hashitoxicosis is a rare variant of Hashimoto’s thyroiditis (HT), characterized by clinical features of hyperthyroidism and the pathological appearance of HT. Here, we present the first case of febrile HE associated with Hashitoxicosis, in a previously healthy adult female, whose manifestation was difficult to distinguish from viral encephalitis or thyroid storm.
Case report A 21-year-old female presented with tonic–clonic seizures followed by spurting vomiting, hyperpyrexia and then disturbance of consciousness for 2 days was first admitted to a local hospital. The peak temperature was higher than 39 °C. The patient was diagnosed with viral meningoencephalitis and treated with antiviral agents and antiepileptic drugs. The symptoms were relieved in 2 days. In the following 2 months, 3 similar periods of deterioration occurred. Symptoms tended to but not limited to occur during
T. Lu A. Wu B. Qin Z. Lu (&) Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Guangzhou, Guangdong Province, China e-mail: [email protected]; [email protected] Z. Zhou Department of Neurology, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui Province, China
menstrual periods. Tremor of both hands was observed 3 days before the second episode. Visual hallucinations were noticed just after the second episode. The patient also gradually developed dysphoria, dystropy and cognitive impairment. Just after the onset of the 4th episode, the patient was admitted to our hospital. On initial assessment, the patient’s body temperature was 37–37.8 °C, the heart rate was 78–134 bpm. Thyroid was enlarged and soft. Babinski sign for both sides and palmomental reflex for the right side were positive. Rigidity of the neck was positive. The patient exhibited confusion with episodes of agitation and panic with visual hallucinations. The cranial MRI was normal. EEG showed diffuse slowing without triphasic potentials or spike waves. CSF pressure was 180 mmH2O. Routine tests revealed elevated total protein content (0.75 g/L). No pleocytosis and oligoclonal bands were detected. Tests for serum markers of infectious, toxic, paraneoplastic and autoimmune etiologies were negative, except weakly positive for antinuclear antibody. An elevated thyroid status was noticed. The serum levels of free 3,5,30 -triodothyronine (FT3), free thyroxin (FT4) and thyroid-stimulating hormone (TSH) were 10.48, 43.10 pmol/L and 0.003 lIU/mL, respectively. High titers of antithyroid peroxidase antibodies (TPO-Ab) and antithyroglobulin antibodies (TGAb) in serum (326 and[500 IU/mL, respectively) and CSF (12.2 and 42.0 IU/mL, respectively) were detected. Thyroid-stimulating hormone receptor antibodies (TR-Ab) were negative in both the serum and CSF. The calculated intrathecal TPO-Ab index was 3.33, and thus was suggestive of autochtone synthesis of thyroid autoantibodies in the CSF. An ultrasound revealed a symmetrically enlarged thyroid with a hypoechoic, heterogeneous echo pattern. A radioactive iodine uptake (RAIU) indicated reduced uptake over the thyroid gland.
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The patient was diagnosed with HE associated with Hashitoxicosis. A high-dose glucocorticoid therapy (methyl-prednisolone 1000 mg i.v. for 3 days and tapered to 12 mg p.o.) was used on day 5. Thiamazole 10 mg twice daily and propranolol 10 mg twice daily were used to control hyperthyroidism. The symptoms were relieved within 24 h. However, TPO-Ab and TG-Ab were 264.8 and [500 IU/mL, respectively on day 11. The patient was discharged on day 12, but had a relapse 1 week later after a long travel and was admitted again. High-dose glucocorticoid therapy was repeated. At discharge, TPO-Ab and TG-Ab were 53 and 378 IU/mL, respectively. Half a year has passed, and the patient remains symptom free. The results of thyroid function tests during hospitalization and follow-up is presented in Table 1.
Discussion The central nervous system (CNS) symptoms of this patient included relapsing generalized seizure, depressed level of consciousness, cognitive impairment and psychiatric symptoms. Examination indicated slow waves in EEG, elevated CSF protein and elevated levels of thyroid antibodies in both serum and CSF. The manifestation perfectly fulfilled the diagnostic criteria for HE [1]. Fever, following seizures, was a notable symptom of this case. This patient was initially misdiagnosed with viral meningitis without proper treatment, thus suffered from multiple attacks of deterioration and developed mental deficiency. So far, only six other cases of febrile HE has been reported, none of them with hyperthyroidism [2–7]. In a chronic progressive course in older subjects, fever tended to occur at the late stage. In an acute or relapse-remitting course, it was one of the first symptoms. Fever tended to occur in severe situation of the disease and indicated a need for emergent medication. The mechanism of fever in HE was unknown. However, it seems to be a result of the
disease itself. Because fever was combined with seizure, confusion, stupor, agitation and hallucination, all of which were symptoms related to the limbic system, we speculated that fever could be a direct result of limbic system injury. Since autoimmune-mediated CNS vasculitis was suggested as a possible underlying mechanism of HE, fever could also be a result of inflammation. In our case, another reasonable differential diagnosis was thyroid storm. The CNS manifestation of thyroid storm includes agitation, delirium, psychosis, stupor, seizure and coma, which could be similar to HE [8]. Burch and Wartofsky have proposed a point scale for the diagnosis of thyroid storm, in which a score of 45 and above is highly suggestive of thyroid storm [9]. Our patient reached a score of 60 on day 2, sufficient for the diagnosis of thyroid storm. However, the thyroid state of our patient did not seem to be sufficient to cause thyroid storm. Thus, thyroid storm was ruled out and only a routine dose of antithyroid drugs was used. Our patient responded well to glucocorticoid but soon had a relapse. The antibody levels do not necessarily correlate with the severity of HE [1]. However, the unchanged levels of antibodies indicated the dose or the period of glucocorticoid was not sufficient and the immune system was not corrected. We supposed that in a specific patient, the levels of antibodies could be helpful in predicting relapse and monitoring the efficacy of the treatments. We reported the first case of febrile HE associated with Hashitoxicosis. High fever and hyperthyroidism made it difficult to distinguish this condition from viral encephalitis or thyroid storm. In cases with symptoms of encephalopathy combined with elevated antithyroid antibodies, HE should be carefully considered. Fever is rare in HE, but it tends to be a sign of severe condition and the need for emergent medication. HE is one of the few treatable encephalopathies. If glucocorticoid is effective, the course should be sufficient and the decrement should be carefully considered. Reduction in the levels of antithyroid antibodies could be a reflection of the efficacy of the therapy.
Table 1 Thyroid function results during hospitalization and follow-up Days from admission
FT3 (normal 2.8–6.3 pmol/L)
FT4 (normal 11.5–22.7 pmol/L)
TSH (normal 0.35–5.5lIU/mL)
TPO-Ab (normal \60 IU/mL)
TG-Ab (normal \60 IU/mL)
Day 2
10.48
43.10
0.003
326
[500
Day 11
11.45
54.10
0.006
264.8
[500
Day 30
12.54
44.57
0.003
40.13
Day 48
6.10
23.11
0.01
53
378
Day 141
3.39
17.24
1.405
44.5
231
Day 222
5.81
18.53
3.243
23.2
79
[500
FT3 free 3,5,30 -triodothyronine, FT4 free thyroxin, TSH thyroid-stimulating hormone, TPO-Ab antithyroid peroxidase antibodies, TG-Ab antithyroglobulin antibodies
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Acta Neurol Belg Conflict of interest
None.
References 1. Afshari M, Afshari ZS, Schuele SU (2012) Pearls & oy-sters: hashimoto encephalopathy. Neurology. 78(22):e134–e137 2. Papathanasopoulos P, Mallioris K, Karanasios P et al (2000) Febrile Hashimoto’s encephalopathy. J Neurol Neurosurg Psychiatry 68(6):795 3. Jacob S, Rajabally YA (2005) Hashimoto’s encephalopathy: steroid resistance and response to intravenous immunoglobulins. J Neurol Neurosurg Psychiatry 76(3):455–456 4. Bonmann E, Prumbaum M, Stippich C et al (2009) Hashimoto encephalopathy: rare cause of stroke in young patient. Neurologist 15(6):342–344
5. Chen N, Qin W, Wei C et al (2011) Time course of Hashimoto’s encephalopathy revealed by MRI: report of two cases. J Neurol Sci 300(1–2):169–172 6. Huang W, Xia C, Chatham M (2011) Infectious disease or Hashimoto’s encephalopathy flares: a case report. Seizure 20(9):717–719 7. Zhao W, Li J, Wang J et al (2011) A case of Hashimoto encephalopathy: clinical manifestation, imaging, pathology, treatment, and prognosis. Neurologist 17(3):141–143 8. Bahn Chair RS, Burch HB, Cooper DS et al (2011) Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 21(6):593–646 9. Burch HB, Wartofsky L (1993) Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am 22(2):263–277
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LETTER TO THE EDITOR
Febrile Hashimoto’s encephalopathy associated with Hashitoxicosis Tingting Lu • Zhiming Zhou • Aimin Wu Bing Qin • Zhengqi Lu
•
Received: 19 January 2015 / Accepted: 24 February 2015 Ó Belgian Neurological Society 2015
Introduction Hashimoto’s encephalopathy (HE) is a rare autoimmune disease characterized by encephalopathy and high titers of antithyroid antibodies [1]. Fever was rarely noticed. Hashitoxicosis is a rare variant of Hashimoto’s thyroiditis (HT), characterized by clinical features of hyperthyroidism and the pathological appearance of HT. Here, we present the first case of febrile HE associated with Hashitoxicosis, in a previously healthy adult female, whose manifestation was difficult to distinguish from viral encephalitis or thyroid storm.
Case report A 21-year-old female presented with tonic–clonic seizures followed by spurting vomiting, hyperpyrexia and then disturbance of consciousness for 2 days was first admitted to a local hospital. The peak temperature was higher than 39 °C. The patient was diagnosed with viral meningoencephalitis and treated with antiviral agents and antiepileptic drugs. The symptoms were relieved in 2 days. In the following 2 months, 3 similar periods of deterioration occurred. Symptoms tended to but not limited to occur during
T. Lu A. Wu B. Qin Z. Lu (&) Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Guangzhou, Guangdong Province, China e-mail: [email protected]; [email protected] Z. Zhou Department of Neurology, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui Province, China
menstrual periods. Tremor of both hands was observed 3 days before the second episode. Visual hallucinations were noticed just after the second episode. The patient also gradually developed dysphoria, dystropy and cognitive impairment. Just after the onset of the 4th episode, the patient was admitted to our hospital. On initial assessment, the patient’s body temperature was 37–37.8 °C, the heart rate was 78–134 bpm. Thyroid was enlarged and soft. Babinski sign for both sides and palmomental reflex for the right side were positive. Rigidity of the neck was positive. The patient exhibited confusion with episodes of agitation and panic with visual hallucinations. The cranial MRI was normal. EEG showed diffuse slowing without triphasic potentials or spike waves. CSF pressure was 180 mmH2O. Routine tests revealed elevated total protein content (0.75 g/L). No pleocytosis and oligoclonal bands were detected. Tests for serum markers of infectious, toxic, paraneoplastic and autoimmune etiologies were negative, except weakly positive for antinuclear antibody. An elevated thyroid status was noticed. The serum levels of free 3,5,30 -triodothyronine (FT3), free thyroxin (FT4) and thyroid-stimulating hormone (TSH) were 10.48, 43.10 pmol/L and 0.003 lIU/mL, respectively. High titers of antithyroid peroxidase antibodies (TPO-Ab) and antithyroglobulin antibodies (TGAb) in serum (326 and[500 IU/mL, respectively) and CSF (12.2 and 42.0 IU/mL, respectively) were detected. Thyroid-stimulating hormone receptor antibodies (TR-Ab) were negative in both the serum and CSF. The calculated intrathecal TPO-Ab index was 3.33, and thus was suggestive of autochtone synthesis of thyroid autoantibodies in the CSF. An ultrasound revealed a symmetrically enlarged thyroid with a hypoechoic, heterogeneous echo pattern. A radioactive iodine uptake (RAIU) indicated reduced uptake over the thyroid gland.
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The patient was diagnosed with HE associated with Hashitoxicosis. A high-dose glucocorticoid therapy (methyl-prednisolone 1000 mg i.v. for 3 days and tapered to 12 mg p.o.) was used on day 5. Thiamazole 10 mg twice daily and propranolol 10 mg twice daily were used to control hyperthyroidism. The symptoms were relieved within 24 h. However, TPO-Ab and TG-Ab were 264.8 and [500 IU/mL, respectively on day 11. The patient was discharged on day 12, but had a relapse 1 week later after a long travel and was admitted again. High-dose glucocorticoid therapy was repeated. At discharge, TPO-Ab and TG-Ab were 53 and 378 IU/mL, respectively. Half a year has passed, and the patient remains symptom free. The results of thyroid function tests during hospitalization and follow-up is presented in Table 1.
Discussion The central nervous system (CNS) symptoms of this patient included relapsing generalized seizure, depressed level of consciousness, cognitive impairment and psychiatric symptoms. Examination indicated slow waves in EEG, elevated CSF protein and elevated levels of thyroid antibodies in both serum and CSF. The manifestation perfectly fulfilled the diagnostic criteria for HE [1]. Fever, following seizures, was a notable symptom of this case. This patient was initially misdiagnosed with viral meningitis without proper treatment, thus suffered from multiple attacks of deterioration and developed mental deficiency. So far, only six other cases of febrile HE has been reported, none of them with hyperthyroidism [2–7]. In a chronic progressive course in older subjects, fever tended to occur at the late stage. In an acute or relapse-remitting course, it was one of the first symptoms. Fever tended to occur in severe situation of the disease and indicated a need for emergent medication. The mechanism of fever in HE was unknown. However, it seems to be a result of the
disease itself. Because fever was combined with seizure, confusion, stupor, agitation and hallucination, all of which were symptoms related to the limbic system, we speculated that fever could be a direct result of limbic system injury. Since autoimmune-mediated CNS vasculitis was suggested as a possible underlying mechanism of HE, fever could also be a result of inflammation. In our case, another reasonable differential diagnosis was thyroid storm. The CNS manifestation of thyroid storm includes agitation, delirium, psychosis, stupor, seizure and coma, which could be similar to HE [8]. Burch and Wartofsky have proposed a point scale for the diagnosis of thyroid storm, in which a score of 45 and above is highly suggestive of thyroid storm [9]. Our patient reached a score of 60 on day 2, sufficient for the diagnosis of thyroid storm. However, the thyroid state of our patient did not seem to be sufficient to cause thyroid storm. Thus, thyroid storm was ruled out and only a routine dose of antithyroid drugs was used. Our patient responded well to glucocorticoid but soon had a relapse. The antibody levels do not necessarily correlate with the severity of HE [1]. However, the unchanged levels of antibodies indicated the dose or the period of glucocorticoid was not sufficient and the immune system was not corrected. We supposed that in a specific patient, the levels of antibodies could be helpful in predicting relapse and monitoring the efficacy of the treatments. We reported the first case of febrile HE associated with Hashitoxicosis. High fever and hyperthyroidism made it difficult to distinguish this condition from viral encephalitis or thyroid storm. In cases with symptoms of encephalopathy combined with elevated antithyroid antibodies, HE should be carefully considered. Fever is rare in HE, but it tends to be a sign of severe condition and the need for emergent medication. HE is one of the few treatable encephalopathies. If glucocorticoid is effective, the course should be sufficient and the decrement should be carefully considered. Reduction in the levels of antithyroid antibodies could be a reflection of the efficacy of the therapy.
Table 1 Thyroid function results during hospitalization and follow-up Days from admission
FT3 (normal 2.8–6.3 pmol/L)
FT4 (normal 11.5–22.7 pmol/L)
TSH (normal 0.35–5.5lIU/mL)
TPO-Ab (normal \60 IU/mL)
TG-Ab (normal \60 IU/mL)
Day 2
10.48
43.10
0.003
326
[500
Day 11
11.45
54.10
0.006
264.8
[500
Day 30
12.54
44.57
0.003
40.13
Day 48
6.10
23.11
0.01
53
378
Day 141
3.39
17.24
1.405
44.5
231
Day 222
5.81
18.53
3.243
23.2
79
[500
FT3 free 3,5,30 -triodothyronine, FT4 free thyroxin, TSH thyroid-stimulating hormone, TPO-Ab antithyroid peroxidase antibodies, TG-Ab antithyroglobulin antibodies
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Acta Neurol Belg Conflict of interest
None.
References 1. Afshari M, Afshari ZS, Schuele SU (2012) Pearls & oy-sters: hashimoto encephalopathy. Neurology. 78(22):e134–e137 2. Papathanasopoulos P, Mallioris K, Karanasios P et al (2000) Febrile Hashimoto’s encephalopathy. J Neurol Neurosurg Psychiatry 68(6):795 3. Jacob S, Rajabally YA (2005) Hashimoto’s encephalopathy: steroid resistance and response to intravenous immunoglobulins. J Neurol Neurosurg Psychiatry 76(3):455–456 4. Bonmann E, Prumbaum M, Stippich C et al (2009) Hashimoto encephalopathy: rare cause of stroke in young patient. Neurologist 15(6):342–344
5. Chen N, Qin W, Wei C et al (2011) Time course of Hashimoto’s encephalopathy revealed by MRI: report of two cases. J Neurol Sci 300(1–2):169–172 6. Huang W, Xia C, Chatham M (2011) Infectious disease or Hashimoto’s encephalopathy flares: a case report. Seizure 20(9):717–719 7. Zhao W, Li J, Wang J et al (2011) A case of Hashimoto encephalopathy: clinical manifestation, imaging, pathology, treatment, and prognosis. Neurologist 17(3):141–143 8. Bahn Chair RS, Burch HB, Cooper DS et al (2011) Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 21(6):593–646 9. Burch HB, Wartofsky L (1993) Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am 22(2):263–277
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