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Clinical Reasoning: Encephalopathy in a 10-Year-Old Boy Lance Rodan and Ingrid Tein Neurology 2012;79;E12-E18 DOI 10.1212/WNL.0B013e31825fdf51

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Clinical Reasoning: Encephalopathy in a 10-Year-Old Boy Lance Rodan and Ingrid Tein Neurology 2012;79;E12-E18 DOI 10.1212/WNL.0B013e31825fdf51 RESIDENT & FELLOW SECTION Clinical Reasoning: Section Editor Encephalopathy in a 10-year-old boy Mitchell S.V. Elkind, MD, MS Lance Rodan, MD SECTION 1 There was no history of recent toxic or medica- Ingrid Tein, MD, A 10-year-old, right-handed boy with a several-day tion exposures, travel, immunizations, sick contacts, FRCPC history of fever and upper respiratory symptoms insect bites, or animal exposures. presented with acute onset headache, emesis, The general review of systems was negative. progressive mental status change, and right-sided Question for consideration: Correspondence & reprint focal seizures. Symptoms developed over approxi- 1. What is your initial differential diagnosis based on this requests to Dr. Rodan: [email protected] mately 3 hours. information? GO TO SECTION 2 From the Hospital for Sick Children, Toronto, Canada. Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article. e12 Copyright © 2012 by AAN Enterprises, Inc. SECTION 2 On family history, the mother has English and Initial differential diagnosis should include infection the father Hungarian heritage. Parents are noncon- (encephalitis or meningitis), inflammation (connec- sanguineous. He has 2 younger twin male siblings tive tissue disease/autoimmune disease, primary or who are healthy and developmentally normal. Family secondary vasculitis, antineuronal antibody mediated history is otherwise unremarkable. encephalopathy), demyelination (e.g., acute dissemi- On the current examination, he was mildly febrile nated encephalomyelitis), a vascular event (ischemic and appeared pale. There was no meningismus. Glas- or hemorrhage), and a malignancy such as a glioma gow Coma Scale (GCS) score was 13 due to con- or lymphoma. fused, but fluent speech. He had a receptive aphasia. The patient was loaded with phenytoin and Pupils were equal and reactive to light and fundi treated empirically with acyclovir and antibiotics were normal. He had a right superior quadrantan- while further history was obtained. opia on visual threat. He had bilateral asymmetric He was the product of a normal pregnancy and ptosis. According to the parents, the ptosis had term delivery. His developmental history was slowly developed over the last 2 years and was rela- normal. tively constant throughout the day, but worsened Two years prior, he had a similar episode of fever when he was ill or fatigued. Smooth pursuit eye and encephalopathy, which was associated with left- movements were normal. He had no facial weakness. sided focal seizures and left hemiparesis. CT at that Hearing was grossly normal bilaterally. Gag and jaw time demonstrated swelling of the right temporal jerk were normal. On the motor examination, he had lobe. He was presumptively diagnosed with herpes an asthenic build. He had bilateral pes cavus and encephalitis, and received a full course of acyclovir. hammertoes. Tone was decreased in the right arm CSF herpes simplex virus (HSV) PCR was negative and leg. Reflexes were 3ϩ in the right arm and leg on 2 occasions. At his discharge from hospital, he and 2ϩ elsewhere. Plantar responses were upgoing had made a nearly complete recovery, with only mild bilaterally. The patient was spontaneously moving all residual left leg weakness. 4 extremities, but had difficulty lifting his right arm Over the 2 years leading to his current admission, and leg against gravity. According to his bedside he continued to have persistent fatigue. Also, it be- nurse, his strength was increasing in the right side came evident that he was having more difficulty in following his last seizure. He withdrew each of his 4 school than previously, and his grades dropped from limbs to nailbed pressure. As to Cs and Ds. In addition, when reviewing his growth curve, he had dropped several percentiles on Question for consideration: his growth curve for both weight and height. 1. Where is the lesion? GO TO SECTION 3 Neurology 79 July 17, 2012 e13 SECTION 3 nucleus, but more likely represents a neuromuscu- The patient likely has involvement of his left tempo- lar process (neuromuscular transmission or myop- ral lobe, including Wernicke area and inferior optic athy). Finally, his pes cavus and hammertoes are radiations. His right hemiparesis is possibly related to possible evidence of a mild chronic polyneurop- a postictal Todd paresis. His seizures could be athy (although the differential diagnosis for these spreading to his ipsilateral motor cortex from his deformities also includes distal myopathy, very temporal lesion, although a second lesion of the chronic myelopathy, inflammatory joint disorders, motor cortex cannot be excluded. His more and familial pes cavus). chronic, bilateral ptosis with sparing of the pupils and extraocular movements could represent a ros- Question for consideration: tral midbrain lesion affecting the central caudal 1. Does this information change your differential diagnosis? GO TO SECTION 4 e14 Neurology 79 July 17, 2012 SECTION 4 Finally, an inborn error metabolism should be Knowledge of a similar prior episode, and the addi- considered. The acute, recurrent presentation pro- tional history of longstanding constitutional symp- voked by intercurrent illness suggests a small mole- toms, cognitive decline, chronic ptosis, and possible cule disorder or disorder of energy metabolism. polyneuropathy brings a new dimension to the dif- Involvement of both CNS and peripheral nervous ferential diagnosis. system, and associated systemic symptoms, are com- A chronic vasculitis (primary or secondary) affect- mon in mitochondrial disease. The history of 2 ing the CNS and peripheral nervous system could be stroke-like episodes would be highly suggestive of considered, but this would be unlikely since the pa- mitochondrial encephalomyopathy, lactic acidosis, tient does not have any other organ, joint, or skin and stroke-like episode (MELAS) syndrome. Certain involvement. fatty acid oxidation (FAO) defects can present with A paraneoplastic disease could also be considered, episodic hypoketotic hypoglycemic encephalopathy, but these are relatively rare in children, with the ex- myopathy, exercise intolerance, and peripheral neu- ception of anti-NMDA encephalitis. ropathy (mitochondrial trifunctional protein defi- Mollaret meningitis or recurrent HSV encephali- ciency and long-chain L-3-hydroxyl-acyl CoA tis (e.g., from inherited Toll-like Receptor 3 muta- dehydrogenase [LCHAD] deficiency), and patients tions) could be considered. His school difficulties can have permanent deficits if they have cerebral in- could be explained as the chronic sequelae of tempo- jury while hypoglycemic, though this tends to be ral lobe damage; however, there was never confirma- generalized and not focal in distribution. Also, ptosis tion of HSV infection and this would not explain his is not a typical feature for FAO disorders. Another peripheral nervous system involvement. potential metabolic etiology for recurrent strokes X-linked Charcot-Marie Tooth Disease (CMT1X) with headaches and cognitive decline is homocystin- from mutations in connection 32 is rarely associated uria, though this is not associated with ptosis, neu- with transient encephalopathy and stroke-like epi- ropathy, exercise intolerance, or the described sodes, but this would not account for the patient’s systemic involvement and is therefore unlikely. systemic symptoms. A chronic toxic exposure could be considered, but Question for consideration: there is no history to support this. 1. What investigations would you order? GO TO SECTION 5 Neurology 79 July 17, 2012 e15 SECTION 5 cortical diffusion restriction. There were also smaller, Complete blood count demonstrated a mild leukocy- ill-defined areas of high fluid-attenuated inversion tosis and normocytic anemia. Blood gas demon- recovery signal of varying ages in the right superior strated a compensated metabolic acidosis. Initial temporal gyrus, right occipital lobe, left prefrontal lactate was 9.1 mmol/L, and remained elevated on gyrus, left superior temporal gyrus, and left postcen- repeat samples. Pyruvate was not performed. Urine tral gyrus. Magnetic resonance spectroscopy (MRS) toxicology screen was negative. showed a lactate peak at 1.33 ppm (arrow). CT head demonstrated a nonenhancing, hy- Initial EEG was remarkable for slowing over the podense mass lesion in the left temporal lobe and a posterior aspect of the left hemisphere. There were small, chronic low density in the right parietal lobe. no periodic lateralizing epileptiform discharges. There was local mass effect, but no midline shift or As a result of the clinical phenotype, genetic test- effacement of quadrigeminal or suprasellar cisterns. ing for mitochondrial DNA (mtDNA) 3243 A3G Radiologic differential diagnosis included tumor, en- tRNA Leu and 3271 T3C tRNA Leu was sent. The cephalitis, or infarct. patient was positive for the 3243 A3G tRNA Leu Lumbar puncture was performed and showed a mutation with a mutation load of 32% in muscle. normal cell count, normal glucose and protein, and a lactate of 5.29 mmol/L (upper limit of normal 2.4). DISCUSSION What is the diagnosis? MELAS refers CSF was sent for bacterial culture and viral PCR to the syndrome of mitochondrial encephalomyopa- (HSV1/2, varicella zoster virus, Epstein-Barr virus, thy, lactic acidosis, and stroke-like episodes. The syn- cytomegalovirus, HHV6, HHV7, HHV8, enterovi- drome was first described by Pavlakis in 1984. The rus, arbovirus including West Nile virus). Antimicro-
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