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case 36
    n engl j med 353;21   www.nejm.orgnovember 24, 2005  The   new england journal of    medicine   2271  case records of the    massachusetts general hospital   Founded by   Richard C. CabotNancy Lee Harris, m.d.,   Editor     Jo-Anne O. Shepard, m.d.   ,  Associate Editor    Stacey M. Ellender,  Assistant Editor    Sally H. Ebeling,  Assistant Editor    Christine C. Peters,  Assistant Editor   Case 36-2005: A 61-Year-Old Woman with Seizure, Disturbed Gait,and Altered Mental Status  Bradford C. Dickerson, M.D., David Holtzman, M.D., Ph.D., P. Ellen Grant, M.D.,and Di Tian, M.D., Ph.D.   From the Departments of Neurology(B.C.D., D.H.) and Pediatrics (D.H.), theDivision of Pediatric Radiology, Departmentof Radiology (P.E.G.), and the Depart-ment of Pathology (D.T.), MassachusettsGeneral Hospital; the Division of Cogni-tive and Behavioral Neurology, Departmentof Neurology, Brigham and Women’s Hos-pital (B.C.D.); and the Departments of Neu-rology (B.C.D., D.H.), Pediatrics (D.H.),Radiology (P.E.G.), and Pathology (D.T.),Harvard Medical School — all in Boston.N Engl J Med 2005;353:2271-80.  Copyright © 2005 Massachusetts Medical Society.  Dr. Ronan Walsh  (Department of Neurology, Brigham and Women’s Hospital): A 61-year-old left-handed woman was admitted to the neurology service of this hospital becauseof a seizure and altered mental status.On the morning of admission, her husband awoke at 4 a.m. to find her thrashing inbed, with rhythmic movements of all four extremities, for two to five minutes. She sub-sequently appeared groggy but alert, with a facial droop, garbled speech, and an inability to follow verbal commands. Emergency-medical-services personnel were called andshe was brought to the emergency department of this hospital and admitted to the neu-rology service.The patient had been in good health, with the exception of mild hypertension for which she took no medications. She worked in retail sales, had smoked until she was35 years of age, and rarely drank alcohol. She was married with four sons, had no sib-lings, and had no family history of stroke or other neurologic illness.Her vital signs were normal except for a blood pressure of 180/76 mm Hg. The weight  was 73 kg and the height 150 cm. The general physical examination revealed no abnor-malities. On neurologic examination, the patient was alert and pleasant but did not follow commands or know the date. When speaking, she made frequent phonemicparaphasic errors and perseverated. She could write but not speak the names of objectson the National Institutes of Health stroke cards and could not repeat spoken words.She read with paraphasic errors and did not follow written commands. Motor exami-nation revealed no pronator drift and full strength in the arms and legs. There was de-creased blink reflex in response to threat on the right. Her extraocular movements werefull. A sensory examination was limited by her aphasia. Reflexes were 2+ throughout, with the left toe going downward on plantar-reflex testing and the right equivocal. Thegait was slightly wide-based but steady with good stride. The serum levels of electrolytes,calcium, phosphorus, and magnesium were normal, as were the results of renal-func-tion tests. The cerebrospinal fluid protein and glucose levels were normal, and the cellcounts showed no abnormalities. Other laboratory-test results are shown in Table 1. presentation of case    n engl j med 353;21   www.nejm.orgnovember 24   , 2005  The   new england journal of    medicine   2272  Phenytoin was administered intravenously. Aurinary tract infection was confirmed and treated with levofloxacin. Computed tomographic (CT)scanning of the brain revealed a focus of low atten-uation in the left temporal lobe. Magnetic resonanceimaging (MRI) disclosed a corresponding regionof bright signal in the left temporal lobe on T   2  - weighted and diffusion-weighted imaging. An elec-troencephalogram revealed periodic lateralizingepileptiform discharges in the left hemisphere withmarked asymmetry in the form of low-amplitudedelta and theta waves on the left. A biopsy of theleft temporal-lobe lesion was performed on thefourth hospital day. An examination of the biopsy specimen disclosed features that were consistent  with ischemic changes.The patient’s speech gradually improved but re-mained severely impaired. She was discharged to arehabilitation facility on the 16th hospital day. Overthe course of the next two months, she was able toperform most activities of daily living, but languagedifficulty and confusion persisted. She was readmit-ted for a repeated brain biopsy, two months later, which showed features identical to the first.For the next six months, she remained aphasicand confused, and she had difficulty recognizingfamily members. She read and wrote at a second-grade level. No further seizure activity occurred.Over a two-day period, worsening aphasia and con-fusion developed, and she was again brought tothe emergency room and admitted to the hospital.The results of the neurologic examination were un-changed from the first admission.A repeated brain MRI revealed a new, right-sided, temporo-occipital lesion that was bright onT   2  -weighted and diffusion-weighted imaging. Elec-troencephalography revealed right-sided parieto-occipital periodic lateralizing epileptiform dis-charges, two separate bursts of activity consistent  with focal electrographic seizures, and generalizedslowing. The phenytoin level was 8 µg per milliliter.Intravenous phenytoin (0.5 g) was given and clo-nazepam was begun. The levels of cerebrospinalfluid protein and glucose and the cell counts werenormal. Other laboratory-test results are shown inTable 1. The patient was treated for a confirmedurinary tract infection. A biopsy specimen of theleft deltoid muscle obtained on the third hospitalday (of the readmission) showed mild myofiber at-rophy and occasional fibers with abnormal NADH–tetrazolium reductase (NADH-TR) staining. Testingof a blood specimen for mitochondrial DNA muta-tions was negative for the seven most commonmutations. The patient was discharged on the fifthhospital day with her language functioning havingreturned to baseline levels.Approximately six weeks after discharge she be-gan to have difficulty hearing, worse on the left sidethan on the right. Two weeks later, she had an epi-sode of tremulousness in the left hand and was re-admitted to the hospital. A new enhancing lesionin the right temporal lobe was seen on MRI. Hersymptoms resolved, and she was discharged afterthree days. Over the course of the next five months,her speech fluency and comprehension deteriorat-ed. She had increasing difficulty with oral intake,frequently regurgitated food and pills, and lost 23kg. Her gait became unsteady, and she could walk only with assistance. She was readmitted to thehospital.The patient’s vital signs were normal. On neu-rologic examination, she was alert but could not answer questions or follow verbal commands. Hergait was shuffling, with small steps, and she re-quired the assistance of one person. The phenytoinlevel was elevated at 25.8 µg per milliliter (normal,5 to 20); phenytoin was withheld and her gait gradually improved. During the hospital stay sheshowed some paranoid behavior and seemed tohave hallucinations or illusions, which improvedafter treatment with quietapine. Thiamine, biotin,coenzyme Q10, folate, riboflavin, vitamin C, and vitamin E were added to the patient’s treatment.Auditory evoked responses in the brain stem con-firmed dysfunction in the peripheral hearing sys-tem, worse on the left side than on the right side.A gastrostomy tube was inserted on the 15thhospital day, and a diagnostic procedure was per-formed.  Table 1.Laboratory-Test Results.Variable (Normal Range)1stAdmission3rdAdmission  Creatine kinase (40–150 U/liter)230Alkaline phosphatase (30–120 U/liter)51179Aspartate aminotransferase (0–35 U/liter)6328Alanine aminotransferase (0–34 U/liter)3725Lactic acid (0.6–1.7 mmol/liter)3.2Cerebrospinal fluid lactate (0.4–2.2 mmol/liter)7.44.6    n engl j med 353;21   www.nejm.orgnovember 24, 2005   case records of the massachusetts general hospital   2273  Dr. Bradford C. Dickerson:  This 61-year-old womanhad an acute neurologic syndrome that began witha seizure and was followed by residual aphasia, which was accompanied by right visual-field loss.This set of focal neurologic deficits localizes thelesion to the left temporo-occipital region. Hyper-tension was the only obvious element of the medi-cal history that predisposed the patient to neurolog-ic disease. At the time of her initial presentation,the differential diagnosis was broad, including cere-brovascular, neoplastic, infectious, inflammatory,and metabolic processes. Given the absence of ahistory of a prodrome (such as a headache, subtleneurologic symptoms, or systemic illness) or pre-disposing conditions (such as autoimmune diseaseor alcoholism), a cerebrovascular insult was highon the list of diagnostic possibilities.Although the development of seizures soon af-ter that of ischemic cerebral infarcts was describedmore than 100 years ago,   1  seizure is the presentingfeature in only 2 to 33 percent of ischemic strokes.   2  However, seizures are common as a presenting fea-ture of other cerebrovascular diseases, includinglobar intracerebral hemorrhage,   3  cerebral venoussinus thrombosis,   4  and hypertensive encephalopa-thy.   5  A neuroimaging study is an essential and ur-gent component of the workup of a patient whopresents to the hospital in this manner; the inter-pretation of the study will heavily influence man-agement of the acute syndrome.May we review the neuroimaging studies?  Dr. P. Ellen Grant:  The MRI obtained on the pa-tient’s first admission (Fig. 1A) shows increasedT   2  -weighted signal in both gray and white matterof the left temporal lobe, indicating increased free water, which results in a local mass effect effacingthe sulci. On the T   1  -weighted images obtained af-ter the administration of contrast material, there isa small region of cortical enhancement, indicatingbreakdown of the blood–brain barrier (Fig. 1B).On diffusion-weighted imaging, there are areas of abnormally bright signal in the left temporal lobe(Fig. 1C), which indicates increased T   2  -weightedsignal, decreased diffusion, or both. The corre-sponding apparent-diffusion-coefficient map (Fig.1D) indicates that the rate of diffusion in the affect-ed cortex is only mildly decreased (10 to 15 percent), whereas the subcortical white matter has increaseddiffusion (approximately twice the normal rate).Decreased diffusion occurs when there is failureor impairment of the sodium–potassium pump.When there is complete failure, necrosis ensues andthe apparent-diffusion-coefficient values are typical-ly decreased by 60 to 80 percent. In this case, the cor-tical apparent-diffusion-coefficient values are mildly  differential diagnosis  Figure 1.Magnetic Resonance Images from the First Admission.  An axial fluid-attenuated inversion recovery image (Panel A) shows increasedsignal and sulcal effacement involving a large portion of the left temporal lobe(arrows). The signal in this region was low on T   1  -weighted imaging and afterthe administration of contrast material (Panel B); there was a small region of cortical enhancement (arrow). Diffusion-weighted imaging is used to exam-ine the properties of the free water to determine whether the water moleculesare moving at a slower rate than normal, as in metabolic dysfunction or fail-ure, or at a faster rate than normal, as in vasogenic edema. Bright signal ondiffusion-weighted imaging can be due to increased T   2  -weighted signal, de-creased diffusion, or both. The diffusion-weighted image (Panel C) showsincreased cortical signal in the anterior left temporal lobe (arrows). The corre-sponding apparent-diffusion-coefficient maps are used to determine whetherthe bright diffusion-weighted-imaging signal is due to decreased diffusionor increased T   2  -weighted signal. Each pixel value on the apparent-diffusion-coefficient map is the rate of water diffusion in that pixel. On the apparent-diffusion-coefficient map (Panel D), the cortical regions have diffusion thatis normal to only slightly decreased (10 to 15 percent), as compared with thenormal contralateral cortex. The subcortical white matter in the anterior lefttemporal lobe (arrows) has increased diffusion (approximately twice the nor-mal rate). ABCD    n engl j med 353;21   www.nejm.orgnovember 24   , 2005  The   new england journal of    medicine   2274  decreased — suggesting that either a small frac-tion of cells is undergoing necrosis or the sodium–potassium pump is partially impaired. Increaseddiffusion occurs in vasogenic edema, and thus theedema is probably affecting the subcortical whitematter. Magnetic resonance spectroscopy showedalmost complete loss of  N   -acetylaspartate, choline,and creatine, but with a markedly elevated lactatepeak. The perfusion study showed symmetric blood volume and blood flow without a clear defect in theleft temporal lobe, which would be atypical in acutestroke. The mean transit times were normal.Eight months later, the left temporal-lobe abnor-mality had evolved into an area of encephalomala-cia, but there was now a right temporo-occipitalabnormality similar in appearance to the left tem-poral-lobe lesion at presentation. The lesion wasbright on diffusion-weighted imaging, and theapparent diffusion coefficient indicated that diffu-sion was only approximately 10 percent decreased.Therefore, much of the bright signal seen on diffu-sion-weighted imaging was due to increased T   2  - weighted signal and only a small amount was dueto a decrease in the apparent diffusion coefficient.Four days later, this lesion had enlarged in size(Fig. 2A and 2B), and on the apparent-diffusion-coefficient map, increased diffusion was evident inthe subcortical white matter, probably owing to vasogenic edema (Fig. 2C). The diffusion in thecortex was normal to approximately 10 to 15 per-cent decreased. Perfusion-weighted imaging, as be-fore, showed no focal deficit, but there was mildly increased cerebral blood flow and decreased meantransit time. A proton magnetic resonance spec-trograph in the affected regions (Fig. 2D) showedreduction of all normal metabolites and a large lac-tate peak indicative of cell loss and anaerobic metab-olism.What disorders present acutely as bright lesionsinvolving cortex and white matter with T   2  -weightedimaging and diffusion-weighted imaging? In anacute stroke, the lesion apparent-diffusion-coeffi-cient values are typically markedly reduced, whereashere the apparent-diffusion-coefficient values wereelevated in the white matter. Also in acute stroke,there is typically a perfusion deficit in the area of theabnormality on diffusion-weighted imaging, where-as here there was no perfusion defect. Occasionally status epilepticus can cause increased diffusion- weighted imaging, but typically only the cortex isinvolved and there is at most only minimal corticaledema without mass effect. In status epilepticus,ipsilateral thalamic involvement is often seen, prob-ably owing to involvement of cortical thalamicloops. Therefore, the imaging findings do not fit  well either with a focal arterial ischemic event or with status epilepticus.These asynchronous lesions, which presentedacutely with cortical and subcortical edema withmildly decreased cortical apparent-diffusion-coef-ficient values and elevated white-matter apparent-diffusion-coefficient values, no perfusion deficit,and marked lactate elevation, are evidence of corti-cal injury, white-matter vasogenic edema, and an-aerobic metabolism in the presence of maintainedperfusion. These findings are strongly suggestive of a metabolic disorder.  Dr. Dickerson:  During this patient’s first hospital-ization, the neuroimaging findings confirmed theclinical localization of the left temporo-occipitallesion, and its characteristics suggested focal meta-bolic dysfunction. In addition, the background elec-trophysiological rhythm in this region was slowed,and there was evidence of persistent cortical irrita-bility. This neurologic syndrome occurred in thecontext of a urinary tract infection, and lumbarpuncture revealed only elevated lactate levels, with-out evidence of a central nervous system infectionor inflammatory response. The unusual constella-tion of findings prompted additional workup, in-cluding magnetic resonance spectroscopy — whichprovided evidence of derangement of cellular energy  within the lesion — and, subsequently, brain biopsy.Eight months later, an acute deterioration of neurologic function, again in the setting of urinary tract infection, was accompanied by similar find-ings on neuroimaging and electroencephalograph-ic study and similar cerebrospinal fluid data. Amuscle-biopsy specimen revealed biochemical ab-normalities suggestive of mitochondrial myopathy,but typical morphologic features were not seen.This patient’s clinical course was one of pro-gressive dementia, marked by intercurrent acuteneurologic episodes and the serial development of multifocal brain lesions. Dysfunction occurred pri-marily in the left perisylvian network for languageand in the occipito-temporal network for object recognition.   6  This pattern is not typical of the com-mon degenerative dementias, such as Alzheimer’sdisease, but would potentially be consistent withcerebrovascular dementia.   7,8  The stepwise courseof this patient’s clinical decline was also consistent  with vascular dementia,   9  but the imaging charac-teristics of the lesions and their extreme electro-
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