Case 1-2009 — A 57-Year-Old Man with Progressive Cognitive Decline

Presentation of Case

Dr. Matthew T. Bianchi (Neurology): A 57-year-old man was transferred to this hospital because of progressive cognitive decline. He had a history of recurrent malignant melanoma of the right conjunctiva and eyelid that was treated at this hospital. Nine days before admission, a nurse from the melanoma clinic who contacted him by telephone for a preappointment interview noted that he was incoherent and unable to answer her questions. Four days later, at a clinic visit, his physician noted that the patient had difficulty understanding the conversation. Options for treatment of the malignant melanoma, including orbital exenteration, were discussed with the patient and his wife.

The next morning, at 3 a.m., his wife awoke to find the patient having convulsive movements in bed. The seizure lasted less than 5 minutes, after which he remained unresponsive. Emergency medical services providers were called; on their arrival 10 minutes later, he had regained consciousness but was incontinent of urine, disoriented, and unable to follow commands. He was transported to the emergency department of another hospital.

On examination, the patient appeared confused. The vital signs were normal, and the oxygen saturation was 97% while he was breathing ambient air. A lumbar puncture was performed; analysis of the fluid revealed no cells and normal levels of protein and glucose, no organisms were detected on Gram's and acid-fast staining, and polymerase-chain-reaction testing for JC virus was negative. Computed tomography (CT) of the brain revealed generalized atrophy; there was no evidence of hemorrhage. An electroencephalogram showed diffuse theta-range background slowing but no epileptiform activity. He was admitted to the hospital. Fluid-attenuated inversion recovery (FLAIR) and T2-weighted magnetic resonance imaging (MRI) of the brain after the administration of gadolinium showed generalized brain atrophy and diffuse white-matter hyperintensity. Lorazepam, haloperidol, phenytoin, levetiracetam, acyclovir, and ceftriaxone were administered. His mental status deteriorated, and he became intermittently agitated. On the fifth day, he was transferred to this hospital.

On further questioning at this hospital, the patient's wife reported that she had noticed occasional episodes of confusion and disorientation during the previous 5 years. During the previous 2 months, she had noticed a change in his behavior, with more frequent episodes of disorientation and progressive impairment in his memory, including forgetting to switch off electrical appliances and having difficulty making out checks and using the computer.

A diagnosis of malignant melanoma of the right eyelid had been made approximately 5 years earlier and was treated with excision; recurrent melanomas on the conjunctiva, lower eyelid, and lacrimal caruncle of the right eye were excised during the next 4 years, most recently 2 months before admission. At that time, CT of the head and chest showed no metastatic lesions. The patient had a history of head trauma and extradural hematoma in infancy and had had a left frontoparietal craniotomy, with no apparent residual cognitive deficit. He had emphysema, hypertension, hyperlipidemia, and depression and had undergone bilateral lens implantations. He had hepatitis C virus (HCV) infection (diagnosed more than 15 years earlier) and had a serum HCV RNA level of 1.6 million IU per milliliter 1 month before admission.

The patient was right-handed, lived with his wife, and had one adult daughter. He smoked cigarettes and drank alcohol socially. In the past, he had abused alcohol and taken cocaine, amphetamines, LSD (lysergic acid diethylamide), and marijuana, as well as intravenous heroin, but he had not used illicit drugs for at least 10 years. He had been an average student and had left school at the age of 16 years to enter the workforce. At the time of hospital admission, he worked in an office position, but in past employment, he had been exposed to organic solvents, primarily industrial degreasers. His father died of kidney cancer, and his mother of colon cancer; one brother died at the age of 59 years of chronic obstructive pulmonary disease, and another brother died at the age of 15 years in a motor vehicle accident. There was no known family history of neurologic disease. He had no known allergies. Medications on admission included metoprolol, haloperidol, lorazepam, ceftriaxone, acyclovir, docusate, levetiracetam, and thiamine.

On examination, the patient was disheveled, cachectic, and intermittently agitated. The temperature was 36.8°C, the pulse 107 beats per minute, the blood pressure 112/90 mm Hg, the respiratory rate 14 breaths per minute, and the oxygen saturation 98% while he was breathing ambient air. He was bald, the right eyelid was scarred, pigmented areas were noted on both irises, the mucous membranes were dry, and several teeth were missing. There were no dysmorphic features. Breath sounds were decreased at both lung bases. There was clubbing of the fingers, and there were multiple tattoos on the skin. Testing of the cranial nerves, motor and sensory systems, coordination, deep-tendon reflexes, plantar responses, and gait disclosed no abnormalities. There were bilateral grasp responses. He recognized his spouse and his caregivers, but he was not oriented to place or time. Simple attention was markedly impaired. He was restless and distracted and needed to be repeatedly redirected to tasks. He spoke continuously and intelligibly but with verbal perseveration. His speech was a fluent, meaningless stream of words, nonwords, and jargon. He could not name common objects, follow simple verbal commands, read, or write. More detailed cognitive testing was impossible because of deficits in attention and language.

A complete blood count was normal, as were levels of serum electrolytes, calcium, phosphorus, magnesium, bilirubin, and troponin T. Coagulation and renal-function tests also were normal. The alkaline phosphatase level was 130 U per liter (reference range, 45 to 115), the aspartate aminotransferase level 54 U per liter (reference range, 10 to 40), and the alanine aminotransferase level 67 U per liter (reference range, 10 to 55). Testing of blood for antibodies to the human immunodeficiency virus, rapid-plasma-reagin testing, and a paraneoplastic antibody panel were negative. A chest radiograph was normal.

On the second hospital day, an electroencephalogram revealed generalized low-amplitude theta-range slowing without superimposed epileptiform activity. The patient's agitation decreased, and haloperidol was stopped. Electrocardiography disclosed first-degree atrioventricular block; metoprolol was stopped, and lisinopril was begun. MRI of the brain after the administration of gadolinium revealed generalized cerebral atrophy, more prominent in the left frontal lobe underlying the craniotomy site, with dilatation of the left lateral ventricle. FLAIR and T2-weighted MRI showed asymmetric hyperintensity within the occipitoparietal and posterior temporal subcortical deep and periventricular white matter, extending into the lateral aspects of the cerebral peduncles and sparing the corticospinal tracts; patchy enhancement was seen along the subcortical U-fibers in both parietal lobes, with relative sparing of the cerebellum and thinning of the corpus callosum. Magnetic resonance angiography showed no vascular occlusions or stenoses.

On the fifth hospital day, a lumbar puncture was performed. Cerebrospinal fluid analysis showed normal cell counts and normal protein and glucose levels; no organisms were evident on Gram's or acid-fast bacilli staining. Testing for antibodies to Borrelia burgdorferi, as well as B. burgdorferi DNA and Venereal Disease Research Laboratory tests were negative. A diagnostic procedure was performed.
Differential Diagnosis

Dr. Daniel J. Costello: I cared for this patient and am aware of the diagnosis. This 57-year-old man with previously stable cognition presented with a 2-month history of deteriorating intellectual function and behavior, which precipitously worsened after a seizure. In retrospect, he had shown intermittent signs of cognitive dysfunction during the preceding 5 years, suggesting an insidious onset of his disease. He had a history of substance abuse, occupational exposure to organic solvents, active HCV infection, and malignant melanoma of the conjunctiva of his right eye, thought to be at significant risk for dissemination. Examination revealed pronounced impairment in attention, language, comportment, and probably memory, which decreased his functional independence. The clinical scenario is that of rapidly progressive dementia, which is defined as a state of progressive, sustained impairment in multiple domains of cognitive function (usually but not always involving memory) occurring in clear consciousness that is sufficiently severe as to impede personal, social, or vocational functions. This is a common and challenging clinical problem, since there are many possible causes (Table 1Table 1Causes of Rapidly Progressive Dementia.), and prompt diagnosis is essential to determine whether it is treatable.

This patient's dementia reflects dysfunction of diffuse cortical structures, subcortical structures, or both. He does not have characteristic clinical abnormalities associated with cerebral cortical dysfunction, such as aphasia, neglect, or apraxia. Impaired attention and forgetfulness, psychomotor slowing, impaired executive and visuospatial skills, change in personality, and emotional disturbance, many of which our patient had, raise the possibility of subcortical dementia due to white-matter disease. Seizures may occasionally occur in white-matter diseases.

The investigative approach to a patient such as this with rapidly progressive dementia requires a thorough clinical history and physical examination and then laboratory tests as summarized in Table 2Table 2Comprehensive Initial Evaluation of a Patient with Rapidly Progressive Dementia.. Testing for rare disorders such as inborn errors of metabolism is sometimes indicated. A brain biopsy is necessary in a small fraction of patients. In this patient, the results of the investigations listed in Table 2 were normal, except for the results of liver-function tests (presumed to be abnormal because of chronic HCV infection) and the findings on electroencephalography.

Dr. Grant, may we review the imaging studies?

Dr. P. Ellen Grant: CT scanning of the brain (Figure 1AFigure 1Imaging of the Brain.) revealed generalized atrophy and decreased attenuation in the peritrigonal regions. There was no evidence of hemorrhage. MRI of the brain (Figure 1B) revealed generalized brain atrophy and symmetric, confluent increased FLAIR and T2-weighted signal in the parietal and temporal lobes, in the posterior body and splenium of the corpus callosum, and in additional areas in the frontal lobes and the lateral midbrain (Figure 1C). Diffusion-weighted imaging (Fig. 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org) shows peripheral linear areas of increased diffusion-weighted-imaging signal in the corpus callosum indicating an outer rim of decreased diffusion. After the administration of contrast material, an incomplete peripheral rim of enhancement was seen around the T2 signal abnormality that crossed through the corpus callosum (Figure 1D).

Dr. Costello: The clinical presentation and imaging abnormalities led to a working diagnosis of a progressive white-matter disease, or leukoencephalopathy. Although the early signs of this disorder are subtle, advanced leukoencephalopathies are associated with progressive abulia, spasticity, frontal-release signs, incontinence, and the development of cortical signs. In the terminal stages, patients progress into a state of akinetic mutism, followed by stupor, coma, and death. This patient presented in the advanced stages of this clinical spectrum.

The most useful diagnostic tool for determining the cause of primary white-matter disease is the pattern of white-matter changes on MRI. Symmetric white-matter changes, seen in this patient, are characteristic of disorders causing diffuse white-matter injury such as symmetrically infiltrative tumors, hereditary white-matter diseases, metabolic injury (anoxia, carbon monoxide poisoning, mitochondrial disorders), or exposure to a white-matter toxin; conversely, asymmetric or multifocal imaging patterns are more likely a result of vascularly mediated or inflammatory disorders or infections.
Symmetric Leukoencephalopathy

The patient had active HCV infection, but active HCV infection, in the absence of secondary vasculitis or cryoglobulinemia, is not associated with progressive white-matter disease. He had a history of recurrent localized malignant melanoma, but there was no evidence of parenchymal metastases or leptomeningeal infiltration. Progressive multifocal leukoencephalopathy was unlikely, since the patient did not seem to be immunocompromised and did not display any cortical neurologic deficits, and the imaging abnormalities were not typical of that disorder. There were no clinical features suggestive of a mitochondrial disorder. There was no history of acute hypoxic injury, carbon monoxide poisoning, radiation therapy, or treatment with chemotherapeutic agents.
Toxic Leukoencephalopathy

The patient had a history of exposure to a number of potential white-matter toxins, including alcohol, cocaine, heroin, and organic solvents, making toxic leukoencephalopathy a prime consideration.1 Toxic leukoencephalopathies can manifest clinically at various intervals after exposure to a toxin.
Substance Abuse

This patient had a history of heavy alcohol use. Although some neurologic syndromes are ascribed to chronic alcohol abuse,2 the fulminant clinical deterioration in this patient, whose current alcohol intake was not excessive, in conjunction with the extensive white-matter abnormalities on MRI is not typical of these syndromes. Cocaine use may lead to cerebral infarcts caused by vasospasm or vasculitis, hemorrhage, seizures, and, in rare cases, a devastating acute toxic leukoencephalopathy.3 These complications typically occur in patients with acute toxic effects from cocaine use. Cocaine overdose may lead to respiratory depression sufficiently severe to cause diffuse anoxic brain injury. It is not clear whether chronic cocaine use alone leads to a distinct toxic leukoencephalopathy.

Inhalation of vaporized heroin (known as “chasing the dragon”) has been associated with a severe acute leukoencephalopathy resulting from extensive damage to white matter, the cerebellum, and basal ganglia,4 possibly due to heroin pyrolysate.5 Heroin leukoencephalopathy is less common with other modes of heroin use, but it has been described with intravenous use, usually in cases of overdose.6 This patient had not used cocaine or vaporized heroin during the preceding decade, making cocaine-related or heroin-related leukoencephalopathy unlikely.
Organic Solvents

This patient had handled degreasers and glues on a regular basis, making the possibility of leukoencephalopathy due to exposure to organic solvents (organic-solvent leukoencephalopathy) a prime consideration.7 Chronic exposure to these highly lipophilic chemicals, either occupationally or through abuse, may disrupt the integrity of myelin and impair neural transmission, resulting in a toxic leukoencephalopathy.8 These leukoencephalopathies generally occur after chronic, moderate-to-high-level exposure, and thus the time course in this case would be consistent with toxic leukoencephalopathy.
Hereditary Leukodystrophies in Adulthood

Although this patient had several risk factors for toxic leukoencephalopathy, the possibility of a hereditary white-matter disorder characterized by loss of myelin from white-matter tracts (leukodystrophy) first presenting in adulthood had to be considered.9 The most common leukodystrophy, X-linked adrenoleukodystrophy (X-ALD), may present in adults, and in this patient the bilateral posterior, symmetric, confluent white-matter signal abnormalities that became slightly enhanced after the administration of gadolinium are consistent with those described in cases of X-ALD. However, the fulminant deterioration, apparent absence of affected family members, and lack of spasticity and sphincter dysfunction are unusual. Metachromatic leukodystrophy may present in adulthood, often with variable combinations of cognitive, behavioral, and neuropsychiatric disturbances, peripheral neuropathy, optic atrophy, and dystonia. Globoid-cell leukodystrophy (Krabbe's disease) is an autosomal recessive lysosomal-storage disorder that may rarely present in adulthood. Imaging abnormalities include a posterior leukoencephalopathy with involvement of the pyramidal tract and corpus callosum. Of the hereditary leukodystrophies, X-ALD is the most plausible, primarily because of the imaging findings, although the clinical presentation was unusual.
Summary

The clinical history and physical examination, in conjunction with the imaging findings, suggest either a toxic leukoencephalopathy or a late presentation of hereditary leukodystrophy, in particular the cerebral form of X-ALD. The patient's condition continued to deteriorate quickly in this hospital. Because of his precipitous clinical decline and the lack of a diagnosis, a stereotactic biopsy was performed, during which a specimen of white matter was obtained from the right parietal region. The intention was to obtain samples from a radiologically abnormal area traversing both the rim of contrast enhancement and the underlying white matter that displayed abnormal signal changes.
Dr. Daniel J. Costello's Diagnosis

Either toxic leukoencephalopathy due to exposure to organic solvents or adult cerebral X-linked adrenoleukodystrophy.
Pathological Discussion

Dr. Pavan K. Auluck: Microscopical examination of the biopsy specimen revealed slightly hypercellular, gliotic white matter with granular eosinophilic material (Figure 2AFigure 2Specimen from a Stereotactic Brain Biopsy.) and patchy loss of myelin (Figure 2B). The presence of granular eosinophilic material raised the suspicion of a storage disorder. Immunohistochemical analysis (Figure 2C) revealed a reduction in the number of axons within the areas of myelin loss. There were no nuclei with viral-type changes suggestive of progressive multifocal leukoencephalopathy, and immunostaining for the large T antigen (directed against epitopes shared by JC virus and simian virus 40 [SV40]) was negative. Numerous macrophages (Figure 2D) filled with granular periodic acid–Schiff (PAS)–positive, diastase-resistant material (Figure 2E) were located within perivascular spaces and scattered throughout the white matter.

The differential diagnosis of PAS-positive macrophages within the brain is limited and includes Whipple's disease, adrenoleukodystrophy, globoid-cell leukodystrophy, metachromatic leukodystrophy, acquired leukoencephalopathy due to toxins, and other hereditary leukodystrophies. In Whipple's disease, the macrophages are typically limited to perivascular spaces without parenchymal infiltration.

Ultrastructural examination (Figure 2F) revealed that the macrophages contained numerous lamellar structures within membrane-bound organelles. No intracellular bacteria (expected in Whipple's disease) were identified. The ultrastructural evidence of membrane-bound lamellar material within macrophages leaves two possibilities: toxic and hereditary metabolic disorders. These neuropathological findings have been described in the context of exposure to organic solvents.10 Among metabolic disorders, this constellation of findings can be seen in late-onset X-ALD11-13 as well as in other genetic causes for which genes have not been identified.14
X-ALD

Dr. Florian S. Eichler: Once the diagnosis of X-ALD was suggested by the pattern of the brain MRI and the brain biopsy, targeted testing of specific organelle function (peroxisome, lysosome, and mitochondrion) was the next step. Very-long-chain fatty acids (more than 20 carbons) are degraded in the peroxisome, and therefore, disorders of the peroxisome such as X-ALD lead to the accumulation of these fatty acids in plasma.15 In this case, testing revealed elevations in the plasma level of very-long-chain fatty acids (Table 3Table 3Results of Plasma Screening for Very-Long-Chain Fatty Acids.). The ABCD1 gene on Xq28, which codes for the peroxisomal membrane protein (not an enzyme) ABCD1, a member of the family of proteins known as ATP-binding cassette transporters, is mutated in X-ALD16,17 (www.x-ald.nl). The mechanisms by which the defect in the ABCD1 gene leads to the accumulation of very-long-chain fatty acids and the associated phenotypic manifestation are poorly understood. In this patient, analysis of the mutation revealed a substitution of arginine by glutamine at amino acid residue 591, confirming the diagnosis of X-ALD. Further testing of cerebrospinal fluid for the DNA of Tropheryma whipplei (which causes Whipple's disease) and testing for NOTCH3 mutations and a lysosomal-enzyme screen were normal.

How unusual is this patient's presentation, and should this diagnosis be considered in all adults with progressive leukoencephalopathy, even those without a family history?18 Leukodystrophies are characterized by normal early development, followed by loss of skills and regression as the myelin deteriorates. Approximately 35% of patients with X-ALD have the childhood cerebral form, with onset of dementia and adrenal insufficiency between 4 and 8 years of age. Seizures are uncommon but may occur. In another 35 to 40% of patients, the disorder presents in young adulthood as a slowly progressive paraparesis, with sphincter disturbances due to the involvement of long tracts in the spinal cord, referred to as adrenomyeloneuropathy. Rapidly progressive inflammatory demyelination develops in 20% of these patients, and they die in 1 to 2 years.19,20

Several unusual features in this patient contributed to the delay in diagnosis. His advanced age at the onset of symptoms is uncommon for X-ALD, as is the rapid progression of cerebral disease. More important, he lacked a history of long-tract signs, and most adults with X-ALD have signs and symptoms of a myeloneuropathy by the time they are his age. In adults, cognitive abnormalities can manifest as neuropsychiatric symptoms, and substance abuse, which was a prominent feature of this patient's history, is not uncommon. However, his long history of drug abuse and exposure to environmental toxins further confounded the diagnostic workup, since it provided a more likely explanation for the onset of new symptoms at his age. An important issue for this patient is that the neuropathology of organic-solvent leukoencephalopathy can be indistinguishable from that of cerebral X-ALD on examination of biopsy specimens.10 In organic-solvent leukoencephalopathy, very-long-chain fatty acids also accumulate in the brain, and the findings of lamellar inclusions in both disorders may reflect this fact. However, the accumulation of these fatty acids in plasma is seen only in cases of X-ALD. Furthermore, the lack of an obvious family history in this case decreased the suspicion for a heritable neurologic disease.

Currently, approximately 2000 patients in the United States have been diagnosed with X-ALD as a result of plasma testing of very-long-chain fatty acids.21 Unfortunately, many adults with leukodystrophies remain undiagnosed, in part because their symptoms are attributed to substance abuse or other disorders such as multiple sclerosis and fibromyalgia.
Discussion of Management

Dr. Eichler: General supportive care and symptomatic treatment for the patient and his family are crucial. Specialist consultation, nursing, schools, rehabilitation, and social agencies are the cornerstones of the care and treatment of patients with X-ALD. Current medical therapies for patients with X-ALD include hormone-replacement therapy for adrenal insufficiency, dietary therapy with Lorenzo's oil (a combination of oleic acid and erucic acid), and hematopoietic stem-cell transplantation.22 Other approaches are still under investigation.

This patient had no signs or symptoms of adrenal insufficiency, and a corticotropin stimulation test was normal, but continued vigilance is necessary. Physical stress and minor illnesses can be detrimental to patients who have adrenoleukodystrophy with adrenal insufficiency. Dietary therapy and hematopoietic stem-cell transplantation are beneficial only for patients who are asymptomatic or in the early stages of the illness.22,23 Unfortunately, this patient's condition, like that of more than half of patients with cerebral involvement, was too advanced to benefit from currently available therapies.

Further questioning of family members revealed that a maternal male cousin had spent many years in a wheelchair; he may have had X-ALD. More important, the patient's daughter was an obligate carrier of the mutation, and her 4-year-old son had an elevated level of very-long-chain fatty acids. He currently has no symptoms and a brain MRI was normal, but he carries a 35% risk of the development of a devastating inflammatory demyelination in the next 6 years. He has been placed on Lorenzo's oil to lower the level of the fatty acids and will receive brain MRIs annually.

In hindsight, there are several lessons to be learned from this case. First, genetic and metabolic markers are useful in the workup of neurologic decline not only in children but also in adults. In addition, a history of drug abuse should not sway one from considering genetic causes of neurologic symptoms. This case reminds us that genetic disorders may present in adulthood. In retrospect, this patient's MRI findings are typical of X-ALD, but this possibility was not seriously considered because of the patient's age and other risk factors for leukoencephalopathy. Screening for genetic disorders, including testing for levels of very-long-chain fatty acids, could prevent the performance of unnecessary brain biopsies in a subgroup of adult patients presenting with cognitive decline. Finally, establishing the diagnosis of a neurogenetic disorder allows for family screening and identification of at-risk family members.

Dr. Costello: The patient's deterioration continued relentlessly and progressed toward a state of akinetic mutism. He died of bronchopneumonia 10 months after his original clinical presentation.
Anatomical Diagnosis

Adult cerebral form of X-linked adrenoleukodystrophy.

Dr. Eichler reports receiving lecture fees from Shire Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.
Source Information

From the Neurology Service (D.J.C., F.S.E.), the Department of Radiology (P.E.G.), and the Department of Pathology (P.K.A.), Massachusetts General Hospital; and the Departments of Neurology (D.J.C., F.S.E.), Radiology (P.E.G.), and Pathology (P.K.A.), Harvard Medical School.

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