Journal of the Neurological Sciences 228 (2005) 1 – 2 www.elsevier.com/locate/jns
Editorial
Possibly, probably definitely, Hashimoto encephalopathy
There are few conditions in clinical neurology as elusive and protean as Hashimoto’s encephalopathy (HE). Since its first description by Brain in 1966 [1] there have been over 90 cases reported in the literature. However, as Mahad et al. [2] point out, in this month’s edition of JNS, only six of those cases present histopathological analysis. The authors of this latest report provide a valuable edition to the spectrum of known pathology in HE. However, it is difficult, if not impossible, to deduce a single disorder from these pathologic reports with no general agreement available on either the phenomenology or interpretation of the findings. Either the search for the true nature of HE will remain a quixotic dream with more and more case reports continually expanding the descriptive horizon or we need to seriously consider a new systematic approach to the clinical diagnosis. It starts with disentangling the common neuropsychiatric symptoms of hypothyroidism from those specific to HE. William Gull first described the neuropsychiatric features of hypothyroidism in 1873, painting a picture of overall mental and physical slowing. The term dmyxedemaT was introduced in 1876 by William Ord, who postulated that the overall apathy, fatigue and weariness of the patients was due to a bjelly-likeQ swelling of connective tissue. Some 15 years later, the Clinical Society of London released its classic report on Myxedema. In that report the disease was characterized by acute or chronic mania in more that 1/3, dementia and melancholia with a preponderance of suspicion and self-accusation in the remainder. Later, Asher used the term dmyxedematous madnessT in order to emphasize the prevalence of florid hallucinosis and agitation in untreated patients with hypothyroidism [3]. Nowadays, florid psychosis as a manifestation of hypothyroidism is very rare and the general behavioral features of hypothyroidism, even in severe cases, are much more consistent with Gull and Ord’s original descriptions of mental slowness, accompanied by somnolence and lethargy. In fact, two thirds of all cases of hypothyroidism in the elderly present with apathy, psychomotor retardation and poor attention [4]. Could it be that at least some of Asher’s original cases with florid behavioral difficulties were inchoate case reports of HE? 0022-510X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2004.09.025
The cause of the stereotypical cognitive slowness in hypothyroidism is unknown but decreased beta-adrenergic receptor sensitivity and decreased central metabolism have been implicated as important chemical and metabolic consequences of thyroid deficiency in the adult brain which may lead to an overall slowness of thought processes. This has been supported by neurophysiological data from EEG studies demonstrating generalized slowing with absence of the normal alpha-rhythm [5]. Despite the prevalence of intellectual impairment, few comprehensive neuropsychogical investigations have been conducted which can identify the specific cognitive domains affected or document the natural history of the cognitive decline. Untreated the hypothyroid patient may present as a rapidly progressive dementia and progress to coma and death. The clinical picture in HE, on the other hand, which has been impressively collated recently by Chong et al. in 2003 [6], instead emphasizes a preponderence of prominent positive symptomatology such as mania, psychosois, seizures, extra pyramidal rigidity, myoclonus and occasional focal stroke-like features. The clinical picture and EEG may mimic those of a prion disease; a diagnostic problem not helped by the fact that many patients may be biochemically euthyroid, the only marker of the disease being elevated thyroid peroxidase antibodies [7,8]. Clinically it is treated, as prion disease was up to recently, as a diagnosis of exclusion with nearly all reports emphasizing long list of pertinent negatives. Broadly, the only way to accommodate diverse histopathological findings is to implicate a vasculopathy, which may cause a non-specific demyelination with or without inflammatory markers. It is the model of prion disease that may point a way out of the spiraling conundrum of additive case reports. There is enough data now to suggest a clinical spectrum from Clinically dpossibleT, through dprobableT to ddefiniteT. Most cases demonstrate a narrow spectrum of EEG findings and the positive predicative value of such findings can be described [9]. Furthermore, the diagnosis cannot be made without positive antibody titres. Thus, clinically probable cases can be classified based on findings of a conducive clinical history; positive antibody titres; transient sharp or triphasic activity and slowing on an EEG with or without
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Editorial
focal T2 abnormalities on magnetic resonance imaging (MRI). The gold standard can be provided by a biopsy proven vasculapthic lesion including demyelination with or without inflammatory markers. This schema leaves room for further diagnostic refinement. For instance, the role of diffusion weighted MRI and magnetic resonance spectroscopy remains to be fully evaluated and there has been an encouraging recent report of a neuronal biomarker (alphaenolase) that has the potential to be as valuable in HE as the 14-3-3 protein has been in prion disease [10] In the last analysis, the importance of clarifying the diagnostic categorization of HE rests with the inescapable clinical finding of rapid remission when treated with moderate to high doses of steroids. A new diagnostic pathway, at the very least, may attune clinicians to treating this disorder positively without waiting for every conceivable test to come back before initiating therapy or worse not treating with immune suppression at all!
References [1] Brain L, Jellinek E, Ball K. Hashimoto’s disease and encephalopathy. Lancet 1966;2:512 – 4. [2] Mahad D.J., Staugaitis S., Ruggieri P., Parisi J., KleinschmidtDemasters B.K., Lassmann H., et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis and primary CNS demyelination. J Neurol Sci 2005;228:3 – 5 (this issue).
[3] Asher R. Myxedematous madness. Br Med J 1949;2:555 – 62. [4] Marsh C. Psychiatric presentations of medical illness. Psychiatr Clin North Am 1997;20(1):181 – 204. [5] Harris R, Della Rovere M, Prior P. Electroencephalographic studies in infants and children with hypothyroidism. Arch Dis Child 1965; 40:612 – 7. [6] Chong JY, Rowland LP, Utiger RD. Hashimoto’s encephalopathy syndrome or myth. Arch Neurol 2003;60:164 – 71. [7] Seipelt M, Zerr I, Nau R, Mollenhauer B, Kropp S, Steinhoff BJ, et al. Hashimoto’s encephalitis as a differential diagnosis of CreutzfeldtJakob disease. J Neurol Neurosurg Psychiatry 1999;66(2):172 – 6. [8] Doherty CP, Schlossmacher M, Torres N, Bromfield E, Samuels MA, Folkerth R. Hashimoto’s enchphalopathy mimicking Creutzfeldt– Jakob disease: brain Biopsy findings. JNNP 2002;73:601 – 2. [9] Henchey R, Cibula J, Helveston W. Electroencephalographic findings in Hashimoto’s encephalopathy. Neurology 1995;45(5):977 – 81. [10] Ochi H, Horiuchi I, Araki N, Toda T, Araki T, Satox K, et al. Proteomic analysis of human barin identifies alpha-enolase as a novel autoantigen in Hashimoto’s encephalopathy. FEBS Lett 2002;528: 197 – 202.
Colin P. Doherty Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland and Department of Neurology, Harvard Medical School, Boston, MA, USA. E-mail address:
[email protected]. Tel.: +1 809 2116/2735; fax: +1 809 2090. 13 September 2004
