showed a clear correlation histochemical COX negativity and mutational load. In our patient, the lack of a family history compatible with maternal inheritance and the presence of myopathy suggest that the T10010C transition arose as a spontaneous event, probably in myogenic stem cells, after germ layer differentiation. Somatic mutations affecting only muscle seem to be more frequent in protein-coding genes of mtDNA, but they have also been detected in tRNA genes.9,10 In fact, lack of maternal inheritance in these patients may well have delayed recognition of their molecular defects because until recently it was generally accepted that point mutations in mtDNA are transmitted maternally. Our patient presented with myopathy manifesting as exercise intolerance; another patient harboring the T10010C mutation in association with a second co-mutation presented with a severe encephalopathy manifested by choreoathetosis, cerebellar ataxia, tetraparesis, and optic atrophy.8 The clinical features seen in our patient are another demonstration of the clinical heterogeneity of mitochondrial diseases.
Acknowledgment The authors thank Dr. Tuan H. Vu for helpful discussion and Lailani Alcaraz-Monzon, Hua-Bin Huang, and Sindu Krishna for technical assistance.
Spontaneous intracranial hypotension causing reversible frontotemporal dementia
References 1. Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2001;2: 342–352. 2. Moraes CT, Ricci E, Bonilla E, DiMauro S, Schon EA. The mitochondrial tRNA (Leu(UUR)) mutation in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS): genetic, biochemical, and morphological correlations in skeletal muscle. Am J Hum Genet 1992;50:934 –949. 3. Bonilla E, Sciacco M, Tanji K, Sparaco M, Petruzzella V, Moraes CT. New morphological approaches for the study of mitochondrial encephalopathies. Brain Pathol 1992;2:113–119. 4. Zeviani M, Moraes CT, DiMauro S, et al. Deletions of mitochondrial DNA in Kearns–Sayre syndrome. Neurology 1988; 38:1339 –1346. 5. Vu TH, Tanji K, Valsamis H, DiMauro S, Bonilla E. Mitochondrial DNA depletion in a patient with long survival. Neurology 1998;51:1190 –1193. 6. Anderson S, Bankier AT, Barrell BG, et al. Sequence and organization of the human mitochondrial genome. Nature 1981;290:457– 465. 7. Tanji K, Bonilla E. Optical imaging techniques (histochemical, immunohistochemical, and in situ hybridization staining methods) to visualize mitochondria. Methods Cell Biol 2001; 65:311–332. 8. Bidooki SK, Johnson MA, Chrzanowska-Lightowlers Z, Bindoff LA, Lightowlers RN. Intracellular mitochondrial triplasmy in a patient with two heteroplasmic base changes. Am J Hum Genet 1997;60:1430 –1438. 9. Andreu AL, Tanji K, Bruno C, et al. Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann Neurol 1999;45:820 – 823. 10. Chinnery PF, Johnson MA, Taylor RW, Lightowlers RN, Turnbull DM. A novel mitochondrial tRNA phenylalanine mutation presenting with acute rhabdomyolysis. Ann Neurol 1997;41:408 – 410.
Abstract—Spontaneous intracranial hypotension (SIH) causes postural headache and neurologic symptoms owing to traction and brain compression. A 66-year-old man with chronic headache and progressive personality and behavioral changes typical of frontotemporal dementia was examined. He had MRI findings of SIH with low CSF pressure. His headache, dementia, and imaging abnormalities abated after treatment with prednisone. SIH can cause reversible frontotemporal dementia, and should be considered when dementia and behavioral changes are accompanied by headache. NEUROLOGY 2002;58:1285–1287
M. Hong, MD, PhD; G.V. Shah, MD; K.M. Adams, PhD; R.S. Turner, MD, PhD; and N.L. Foster, MD
Spontaneous intracranial hypotension (SIH) is a syndrome characterized by postural headaches and CSF hypovolemia.1 By definition, no preceding events such as lumbar puncture, back trauma, or operative
From the Departments of Neurology (Drs. Hong, Turner, and Foster), Radiology (Dr. Shah), and Psychiatry (Dr. Adams), University of Michigan, School of Medicine, Ann Arbor, MI. Supported in part by the Michigan Alzheimer’s Disease Research Center (NIH grant P50-AG08671). Received September 4, 2001. Accepted in final form January 7, 2002. Address correspondence and reprint requests to Dr. Norman L. Foster, Department of Neurology, University of Michigan, 1920 Taubman, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0316; e-mail:
[email protected]
procedures are present. Typical brain MRI findings include diffuse symmetric dural gadolinium enhancement (also known as pachymeningitis), effacement of sulci, obliteration of basilar cisterns, descent of midline structures, enlarged dural sinuses, tonsillar herniation, and subdural hygromas.1 The most common symptom of SIH is insidious onset of orthostatic headache, which often evolves into chronic daily headache. In addition, other symptoms may occur including visual field deficits, transient visual obscuration, facial numbness, sixth-nerve palsy, vertigo, tinnitus, nausea, vomiting, and rarely stupor, cervical myelopathy, and parkinsonism.1-4 The diagnosis of SIH is confirmed by finding low CSF opening Copyright © 2002 by AAN Enterprises, Inc.
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Figure. Initial and repeat (8 months later) brain MRI studies. Gadoliniumenhanced, T1-weighted images in the initial study (A,B) show diffuse meningeal thickening and enhancement (pachymeningitis) extending into the cervical spinal canal (A). There is crowding of posterior fossa structures and lateral compression and distortion of midbrain (B). In a repeat study 8 months later (C,D), there is return of the normal contour of the midbrain (D) and decrease in the meningeal thickening at the high convexity (C) and tentorial reflection (D).
pressure on lumbar puncture in conjunction with imaging findings of “sagging brain.” The symptoms of SIH can resolve after treatment with corticosteroids.1,5,6 This article reports a patient with typical imaging and clinical features of SIH who also had progressive personality and behavior changes with memory loss. Case report. We evaluated a 66-year-old, right-handed, retired electrician with an 18-month history of progressive personality and behavioral changes, memory decline, and chronic daily headache. His wife noticed that in dramatic contrast to his premorbid personality, his social manners became increasingly inappropriate and he frequently uttered offensive and sexually explicit comments in public situations. He also made several bad financial decisions, including purchasing a home without consulting his wife. He became quite subdued and inactive at home spending up to 12 hours a day in bed. He ignored his personal hygiene. He lost his previous interest in reading and watching television and took up cigarette smoking again after having quit for 8 years. His appetite was poor and he lost 10 kg of weight over 5 months. In addition, he had difficulty remembering recent events and repeated the same questions. He became lost while driving. He had chronic, daily bifrontal headaches, but could not describe the nature of the pain. However, his wife noticed that he did not complain of headache while lying supine. He was initially diagnosed with depression, but did not respond to antidepressants. The results of the patient’s physical and general neurologic examination were normal. His gait, motor strength, 1286
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muscle tone, and reflexes were normal. There were no frontal release signs or meningismus. His mental status examination was remarkable for a lack of insight into his personality changes, and he alternated between affability and irritation. He became boisterous at times. When shown a picture of a fork he said, “Fork, like fork you.” He had to be encouraged throughout the examination, but when exhorted to greater effort, he challenged back, “What are you going to do? Lock me up?” Neuropsychological testing demonstrated mild declines in overall intellectual ability and memory, with particularly prominent impairments in concept formation and “frontal” tasks. He had a Mini-Mental State Examination (MMSE) score of 21 (4th percentile) and a Wechsler Adult Intelligence Scale verbal IQ (VIQ) of 84 (14th percentile). He could not complete any category in the Wisconsin Card Sorting Test (WCST; normal ⬎ 3) and made 45 perseverative errors (normal ⫽ 0). Trail Making Tasks A (1st percentile) and B (22th percentile) were performed slowly with errors. There was marked disinhibition and perseveration, but no evidence of depression. Results of laboratory blood tests were normal, including vitamin B12, folate, VDRL/FTA, erythrocyte sedimentation rate, anti-nuclear antibody, rheumatoid factor, serum angiotensin-converting enzyme, and liver, renal, and thyroid function tests. A brain MRI scan showed diffuse meningeal thickening and enhancement (pachymeningitis) that extended into the cervical spinal canal (figure). In addition, there was crowding of posterior fossa structures and descent of cerebellar tonsils. A lumbar puncture showed an opening pressure of 6 cm H2O. CSF cell count and glucose were normal. CSF protein was slightly ele-
vated at 79 mg/dL. CSF bacterial and fungal cultures and cytology were all negative. No CSF leakage was found on a radioisotope cisternogram. A SPECT brain perfusion scan was normal. A right frontal meningeal biopsy revealed an increased number of thick walled vessels in the dura and fibrous connective tissue in the pia. Treatment began with a 2-week tapering course of prednisone, starting at 80 mg/d. This led to significant functional improvement and resolution of headache. However, his symptoms recurred when treatment was discontinued. Prednisone was resumed at a dose of 60 mg/day. He again had a dramatic improvement over 2 weeks. This time his improvement was sustained as his prednisone dose was slowly tapered over 4 months. Subsequently, he has returned to doing household chores and performing tasks on his own initiative. His personality has returned to his premorbid state and he demonstrated insight and selfawareness. He is no longer socially inappropriate, and has normal personal hygiene. Repeat neuropsychological testing showed marked improvement of his “frontal” functions and overall intellect. His MMSE improved to 25 (14th percentile) and VIQ to 106 (66th percentile). He was able to complete two categories on the WCST with much fewer (nine) perseverative errors. Significant improvement of pachymeningitis and resolution of brain sagging were revealed by a repeat MRI (see the figure). His behavior and cognitive symptoms have continued to improve 6 months after the end of prednisone treatment.
Discussion. Our patient had the typical clinical and imaging features of SIH. He had chronic postural headache and MRI evidence of pachymeningitis with descent of brain structures and a low CSF opening pressure. The meningeal biopsy helped to exclude other causes of abnormal pachymeningeal enhancement, such as inflammatory, granulomatous, and neoplastic diseases,7 and there was no alternative explanation for his CSF hypovolemia. There was no history of head trauma, lumbar puncture, or surgical procedure before onset of his symptoms. Although CSF leakage such as spinal meningeal diverticula and dural tear sometimes are identified in patients with SIH,1,2,8 the cause of CSF hypovolemia usually remains uncertain just as in the current case. CSF hyperabsorption is one proposed explanation.5 Unusually rapid CSF clearance of radioactive tracer and pronounced elevation of blood tracer level have been demonstrated in SIH.5 In these cases, treatment with corticosteroids is effective.5,6 The radiographic findings of SIH are a result of CSF hypovolemia and are explained by the Monro–Kellie doctrine, which holds that the sum of volumes of brain, CSF, and intracranial blood remains constant.1,9 With the loss of CSF, there is compensatory dilatation of dural venous spaces. Because dural venous endothelial cells lack tight junctions, there is migration of fluid into the meninges that can be demonstrated on MRI by meningeal thickening and diffusion of contrast into the dura. The mechanisms by which prednisone improves SIH are unknown. It is possible that its benefits are due to altering the char-
acteristics of endothelium or its anti-inflammatory effects. Despite having otherwise typical features of SIH, dementia and behavioral changes were the predominant symptoms in the current patient. The clinical and neuropsychological features of his dementia were typical for frontotemporal dementia.10 His most salient abnormalities were disinhibition, personality changes, impaired judgment and executive functions, in contrast to milder deficits in memory, language, and visuospatial processing. Although without a postmortem examination it is not possible to completely exclude an underlying neurodegenerative disease; the normal SPECT scan and the reversal of his behavioral and cognitive impairment in a relatively brief period with prednisone treatment make this unlikely. The temporal correlation between the current patient’s clinical and functional improvement and the improvement of posture headaches and MRI findings strongly argues that his frontotemporal dementia was caused by SIH. The mechanism by which intracranial CSF hypovolemia caused this patient’s cognitive impairment is uncertain. Symptoms such as vertigo, tinnitus, stupor, and encephalopathy can be explained by the loss of hydrologic support of the brain by the CSF causing the descent of the brain in the cranial vault with traction on cranial nerves and cervical nerve roots, and compression of midline structures.1,2,9 A similar compression of the frontal and temporal cortices caused by caudal “sagging” of the brain could be the cause of frontotemporal dementia. Patients with symptoms of frontotemporal dementia and headache should have an MRI scan with a careful review for signs of pachymeningitis and CSF hypovolemia. References 1. Mokri B. Spontaneous cerebrospinal fluid leaks: from intracranial hypotension to cerebrospinal fluid hypovolemiaevolution of a concept. Mayo Clin Proc 1999;74:1113–1123. 2. Pleasure SJ, Abosh A, Friedman J, et al. Spontaneous intracranial hypotension resulting in stupor caused by diencephalic compression. Neurology 1998;50:1854 –1857. 3. Chung SJ, Kim JS, Lee MC. Syndrome of cerebral spinal fluid hypovolemia: clinical and imaging features and outcome. Neurology 2000;55:1321–1327. 4. Pakiam AS, Lee C, Lang AE. Intracranial hypotension with Parkinsonism, ataxia, and bulbar weakness. Arch Neurol 1999;56:869 – 872. 5. Kraemar G, Hanns HC, Eissner D. CSF hyperabsorption: a cause of spontaneous low CSF pressure headache. Neurology 1987;37(suppl 1):238. Abstract. 6. Murros K, Fogelholm R. Spontaneous intracranial hypotension with slit ventricles. J Neurol Neurosurg Psych 1983;46: 1149 –1151. 7. Bang OY, Kim DI, Yoon SR, Choi IS. Idiopathic hypertrophic pachymeningeal lesions. Euro Neurol 1998;39:49 –56. 8. Fishman RA, Dillon WP. Dural enhancement and cerebral displacement secondary to intracranial hypotension. Neurology 1993;43:609 – 611. 9. Mokri B. The Monro-Kellie hypothesis: applications in CSF volume depletion. Neurology 2001;56:1746 –1748. 10. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration-a consensus on clinical diagnostic criteria. Neurology 1998;51:1546 –1554.
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