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ARTICLES: H. Tada, J. Takanashi, A. J. Barkovich, H. Oba, M. Maeda, H. Tsukahara, M. Suzuki, T. Yamamoto, T. Shimono, T. Ichiyama, T. Taoka, O. Sohma, H. Yoshikawa, and Y. Kohno Clinically mild encephalitis/encephalopathy with a reversible splenial lesion Neurology 2004; 63: 1854-1858 [Abstract] [Full text] [PDF]

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Reply to Shiihara et al and Doherty et al

Jun-ichi Takanashi, Hiroko Tada, MD, A. James Barkovich, MD   (27 December 2004)

Clinically mild encephalitis/encephalopathy with a reversible splenial lesion

Michael J Doherty, Nate F. Watson, Sumi Jayadev, Ravi S Konchada, Dan K Hallam   (27 December 2004)

Clinically mild encephalitis/encephalopathy with a reversible splenial lesion

Takashi Shiihara, Mitsuhiro Kato, Kiyoshi Hayasaka,   (27 December 2004)

Reply to Shiihara et al and Doherty et al 27 December 2004
Jun-ichi Takanashi, MD Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan, Hiroko Tada, MD, A. James Barkovich, MD Send Correspondence to journal: Re: Reply to Shiihara et al and Doherty et al jtaka{at}faculty.chiba-u.jp Jun-ichi Takanashi, et al.	We thank Shiihara et al for their interesting comments concerning the possible role of mitochondrial dysfunction and elevation of inflammatory cytokines in the generation of the splenial lesions. In 15 patients in our study, IL-6 was measured in one patient (patient 2), showing mild elevation of IL-6 (11.5 pg/ml, normal less than 9.7). [1] Lactate in blood or CSF was normal in the three patients so examined (patients 10 and 15 in reference 1; patient 1 in reference 6). IL-6 or other inflammatory cytokines are usually elevated in influenza-associated encephalitis/encephalopathy, in parallel with clinical severity. [7] But a reversible splenial lesion was rarely observed in a few clinically mild cases of influenza-associated encephalopathy. [1,6] Therefore, we believe it is unlikely that elevation of IL-6 plays a direct role in the pathogenesis of the splenial lesion. It will be interesting to see whether mitochondrial dysfunction or lactate elevation in the splenium, or elevation of cytokines in CSF are present in patients with splenial lesions in the future. We thank Dr. Doherty et al for adding this interesting data and observations. We agree that patients with a reversible splenial lesion rarely present with neurological findings of hemispheric disconnection. We could not find any clinical evidence of hemispheric disconnection in our 15 patients. [1] Perhaps most of the patients presented with disorders of consciousness, thus neurological examination could not be fully assessed, especially in association with the young age of the affected patients. The patients in our study were reviewed retrospectively. We excluded a patient taking oral antiepileptic drugs because of another potential cause for the splenial lesion. This bias of the enrolled patients might explain the high frequency of disorders of consciousness. We do not know what role or roles the splenium may play in moderating encephalopathy, confusion or delirium. References 6. Takanashi J, Barkovich AJ, Yamaguchi K, Kahno Y. Influenza encephalopathy with a reversible lesion in the splenium of the corpus callosum. AJNR Am J Neuroradiol 2004; 25: 798-802. 7. Aiba H, Mochizuki M, Kimura M, Hojo H. Predictive value of serum interleukin-6 level in influenza virus-associated encephalopathy. Neurology 2001; 57: 295-299.
Clinically mild encephalitis/encephalopathy with a reversible splenial lesion 27 December 2004
Michael J Doherty, Swedish Neuroscience Institute and the University of Washington Department of Neurology 801 Broadway Suite 901, Seattle, WA 98122, Nate F. Watson, Sumi Jayadev, Ravi S Konchada, Dan K Hallam Send Correspondence to journal: Re: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion michael.doherty{at}swedish.org Michael J Doherty, et al.	Tada et al reported clinical scenarios where MRI-evident midline splenium lesions are seen, particularly with diffusion weighted images (DWI).[1] We recently reviewed nine similar cases of MRI-evident splenium changes along with 48 other reported cases.[2] It is surprising that the bulk of the cases with splenium injury do not show clinical evidence of hemispheric disconnection (apraxias of the left hand, pseudoneglect, alien left hand, astereognosis, agraphia, alexia, visual apraxias, hemaniopsia etc.) Of 57 cases examined, 25% had findings suggestive of disconnection. The most common finding (60% of patients) was delirium, confusion, agitation or encephalopathy. Tada et al's study suggests a similar percentage (8/15 "encephalopathic" with 4 additional patients described as "delirious" i.e. 80%). It is interesting that such poorly localizable clinical findings as "delirium", "encephalopathy", "confusion" or "agitation" might be associated with a consistent, very discrete, and small radiological finding. Could the authors speculate on what roles the splenium may play in moderating encephalopathy, confusion or delirium? Furthermore, did they find a similarly low percentage of neurological findings of hemispheric disconnection? References 1) Tada H, Takanashi J, Barkovich AJ, et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion Neurology 2004 63: 1854-1858. 2) Doherty MJ, Jayadev S, Konchada R, Hallam D, Watson NF. What clinical implications might splenium damage have? Archives of Neurology, 2005 (in press).
Clinically mild encephalitis/encephalopathy with a reversible splenial lesion 27 December 2004
Takashi Shiihara, Department of Pediatrics, Yamagata University School of Medicine 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan, Mitsuhiro Kato, Kiyoshi Hayasaka, Send Correspondence to journal: Re: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion shiihara{at}med.id.yamagata-u.ac.jp Takashi Shiihara, et al.	Tada et al [1] reported patients with encephalitis/encephalopathy showing a reversible splenial lesion and an excellent prognosis. The etiology is heterogeneous and includes seizures or antiepileptic drugs as well as viral infections. We report a patient with a reversible splenial lesion, who demonstrated a mitochondrial DNA mutation as well as CSF cytokine elevation and discuss the pathological mechanism. The 16 year-old patient was the third child of healthy non-consanguineous parents. She had mild neuropathy with foot deformity and muscle weakness after infancy. She also had intercurrent dizziness. Muscle biopsy demonstrated a normal histology but also showed a mitochondrial DNA mutation 8993 T>G. She hardly walked after three weeks of diarrhea but there was no change in serum electrolytes or motor nerve conduction studies. Brain MRI after 4 days showed an isolated ovoid lesion in the central portion of the splenium of the corpus callosum. CSF examinations demonstrated elevations of lactate and interleukin-6 (IL-6) to 27.8 mg/dl and 66.4 (normal <9.7) pg/ml. Specific pathogen was not identified on cultures, PCR or antibody assays. The splenial lesion completely disappeared after 8 days and gait disturbance was recovered within a month. The mitochondrial DNA mutation 8993 T>G is located within the gene for adenosine triphosphate (ATP) synthase subunit 6 and would decrease the capacity for ATP synthesis. [2] In addition, IL-6 directly inhibits ATP synthesis and limits the mitochondrial energy supply. [3] However, 5- fluorouracil is known to cause leukoencephalopathy with a splenial lesion and lactic acidosis. [4] Derivatives of 5-fluorouracil inhibit the activity of aconitase, which converts citrate to isocitrate, resulting in a malfunction of the tricarboxylic acid cycle. [5] Taken together, the mitochondrial dysfunction induced by the CNS cytokine elevation could play a key role in the splenial lesion seen in our patient. We suggest that studies of cytokines or mitochondrial functions, such as lactate or magnetic resonance spectroscopy, would clarify the pathogenesis of such splenial lesions. References 1. Tada H, Takanashi J, Barkovich AJ, et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 2004;63: 1854 2. Nijtmans LG, Henderson NS, Attardi G, Holt IJ. Impaired ATP synthase assembly associated with a mutation in the human ATP synthase subunit 6 gene. J Biol Chem 2001;276:6755-6762. 3. Berthiaume F, MacDonald AD, Kang YH, Yarmush ML. Control analysis of mitochondrial metabolism in intact hepatocytes: effect of interleukin- 1beta and interleukin-6. Metab Eng 2003;5:108-123 4. Tha KK, Terae S, Sugiura M, et al. Diffusion-weighted magnetic resonance imaging in early stage of 5-fluorouracil-induced leukoencephalopathy. Acta Neurol Scand. 2002;106:379-86. 5. Matsubara I, Kamiya J, Imai S.Cardiotoxic effects of 5-fluorouracil in the guinea pig. Jpn J Pharmacol 1980;30:871-9