A case of subcortical dementia due to sarcoidosis of the hypothalamus and fornices

BRAIN AND COGNITION 2, 189-198 (1983)

A Case of Subcortical Dementia Due to Sarcoidosis of the Hypothalamus and Fornices

DANIEL B. HIER, CHINNAMMA THOMAS, AND ANDREA G. SHINDLER

Michael Reese Hospital and Medical Center

A patient with sarcoidosis involving predominantly the hypothalamus and fomices was evaluated for dementia. He showed a relative sparing of fund of knowledge and orientation. Memory skills, particularly short-term memory, were severely impaired. Behavioral changes included apathy and a lack of spontaneity. Insight was relatively preserved. The pattern of his deficits showed some similarities to the pattern reported in patients with Huntington’s disease and was different from that described in Alzheimer’s disease. The dementia caused by subcortical pathology may differ in important respects from that caused by diffuse cortical dysfunction.

INTRODUCTION

Dementias differ with regard to both etiology and topography. There is some interest in determining whether the pattern of cognitive decline in dementia varies according to the topography of the injury. Alzheimer’s disease (characterized by a progressive loss of neurons in the grey matter) is an example of a cortical dementia. On the other hand, the search examples of subcortical dementia has been more difficult. The subcortical structures include the deep white matter, the basal ganglia (caudate, thalamus, putamem, and globus pallidus, and subthalamic nuclei), mammillary bodies, fornix, amygdala, and the brainstem. A variety of diseases including Parkinson’s disease, Huntington’s disease, and progressive supranuclear palsy may affect these subcortical structures to varying extents (Albert, 1978). Mental changes have been described in each of these diseases (Pirozzolo et al., 1982; Boiler, 1980; Kimura, Barnett, & Burkhart, 1981; Butters, Sax, Montgomery & Tarlow, 1978). It has been suggested that the dementia of progressive supranuclear palsy (Albert, Feldman,

Supported in part by the Retirement Research Foundation. Dr. Hier was a recipient of the Milton R. Rosenthal Award of the Michael Reese Hospital and Medical Research Institute Council. Send requests for reprints to Daniel B. Hier, M.D., Behavioral Neurology Unit, Department of Neurology, Michael Reese Hospital and Medical Center, 2900 S. Ellis Ave., Chicago, III. 60616.

189 0278-2626/83 $3 .OO

Copyright 6 1983 by Academic Press. Inc. All rights of reproduction in any form resewed.

190 HIER, THOMAS, AND SHINDLER

& Willis, 1974) and the dementia of Huntington’s disease (Caine, Hunt, Weingarten & Ebert, 1978; Kim, Morrow, & Boller, 1982) differ in important respects from that of Alzheimer’s disease. On the other hand, most evidence suggests that the dementia of Parkinson’s disease is due to coexisting Alzheimer’s disease in the cerebral cortex (Boller, 1980; Hakim & Mathieson, 1979; Sroka, Elizan, Yahr, Burger, & Mendoza, 1981).

Sarcoidosis is a granulomatous (inflammatory) disease of unknown etiology. The central nervous system is involved in about 5% of cases (Delaney, 1977). When sarcoid affects the brain, it often has a predilection for deep subcortical structures (particularly the hypothalamus). Dementia has been described in sarcoid of the brain, but its clinical picture has not been delineated in detail (Cordingley et al., 1981). Furthermore, in some cases of CNS sarcoid dementia may reflect the presence of hy- drocephaius (Ho, Berenberg, Kim, & Dal Canto, 1979). We now report mental changes in a 40-year-old man with central nervous system sarcoidosis. Postmortem examination of the brain showed lesions that were largely confined to the hypothalamus and fornices. Comparison of the mental changes in this man with those found in Alzheimer’s disease suggest that the profile of deficits in dementia due to disease of subcortical structures differs in important respects from the dementia that occurs after diffuse cortical injury.

REPORT OF A CASE

D.T., a 40-year-old right-handed black man, was admitted for evaluation of recurrent spells of neurologic dysfunction.

The patient had a history of SC hemoglobinopathy. In March of 1979 he was admitted to Cook County Hospital for evaluation of malaise and arthralgias. In November of 1979, he was admitted to the Mayo Clinic for evaluation of aseptic necrosis of both femoral heads and decreased libido. While at the Mayo Clinic, he had a transient neurologic spell (10 min in duration) consisting of dysarthria, numbness of the right hand and face, and visual scotomata. The spell was followed by a right temporal headache. He was also noted to have panhypopituitarism with low levels of testosterone, thyroid hormone, luteinizing-releasing hormone, and cor- tisol. A computerized tomographic (CT) scan of the brain was normal. Spinal fluid examination in May of 1980 showed 143 white blood cells (82% mononuclear cells), a CSF protein of 168, and a CSF glucose of 40.

The transient neurologic spells recurred, first monthly, then weekly. The spells were brief and stereotyped with right-sided numbness and tingling associated with dysarthria. In July of 1980, he had a somewhat different spell. Although the spell began with dysarthria and right-sided numbness, he later complained of visual difficulties and told his wife “I can’t hear you.” He then fell back into bed unresponsive. The next day

SUBCORTICAL DEMENTIA 191

his wife noted that his thinking was abnormal and that he had difficulty playing cards. He was admitted to Michael Reese Hospital. Neurological examination showed an alert but dysarthric man. Speech was fluent. He was cooperative but quite apathetic. There was little spontaneity of either speech or movement. He showed good insight into his deficits noting that his memory was poor and that he was no longer able to calculate (he worked as an accountant). His attention span was reduced and he showed difficulties in concentrating during psychological testing. He was easily frustrated and showed irritation at his inability to successfully answer test items. Speech was fluent with normal grammatical structure. Repetition of short phrases and naming of objects was intact. Psychometric testing showed relatively intact vocabulary, fund of knowledge, and orientation (Tables 1 and 2). Short-term memory, new learning ability, and visuospatial skills were impaired. Motor, sensory, cranial nerve, and coordination testing were normal. Deep tendon reflexes were normal. Spinal tap revealed a CSF protein of 282 and a CSF glucose of 34. Cell count in the CSF showed 198 white cells (96% lymphocytes). An elec- trocephalogram showed mild generalized slowing.

A CT scan of the brain and a cerebral angiogram were normal. A radionuclide (WmTc-DTPA) brain scan was consistent with a diffuse inflammatory process. His mental function gradually improved and he was subsequently discharged on thyroid and cortisone replacement therapy. There were subsequent fluctuations in his mental abilities (Tables 1 and 2). In September of 1980, he was readmitted for excrutiating low back pain. On the day after admission he was noted to be lethargic and his temperature rose to 40°C. He quickly lapsed into coma. Neurologic examination revealed a flaccid quadriplegia. There was no response to pain. No extraocular movements could be elicited to the doll’s head maneuver. Cornea1 reflexes were preserved. A brain CT scan was normal. The spinal fluid opening pressure was 140 mm of water. The CSF cell count was 110 white cells (95% mononuclear) and 3100 red cells. The CSF protein

TABLE 1 PERFORMANCE OF D.T. ON WECHSLER MEMORY SCALE (RAW SCORES)

Test 7/l 2180 7117180 g/12/80 8129180

Current Information 5 6 5 5 Orientation 5 5 5 4 Mental Control 5 6 8 3 Verbal Memory 4.5 10 12.5 6.5 Digits Forward 4 5 6 4 Digits Backward 0 3 4 0 Visual Reproduction 3 8 11 6 Paired Associates 6 10 12 6 Memory Quotient 63 90 10.5 66


TABLE 2 PERFORMANCE OF D.T. ON SELECTED SUBTESTS

FROM WECHSLER ADULT INTELLIGENCE

SCALE (SCALED SCORES)

Subset 7112182 7117182

Information 8 12 Digit Span 2 6 Vocabulary 10 14 Picture Completion 6 9 Block Design 3 6

was 130 and the CSF glucose was 67. The patient’s blood pressure dropped precipitously and he developed shock and died. The cause of death was felt to be massive fat embolism to the lungs due to extensive bone necrosis (possibly related to his SC hemoglobin disease).

Psychometric testing. D.T. was examined four times in the 2 months prior to his death. On four occasions the Wechsler Memory Scale (WMS) was administered (Wechsler, 1945) and on two occasions selected subtests from the Wechsler Adult Intelligence Scale (WAIS) (Wechsler, 1955) were administered (Tables 1 and 2). The performance of D.T. on these tests was compared to the performance of 20 subjects with known Alz- heimer’s disease and 20 healthy control subjects (Table 3).

Neuropathological jindings. The brain weighed 1200 g. The meninges were mildly thickened over the hemispheres, but more opaque and milky in the interpeduncular fossa and at the base. Multiple tiny white plaques were seen along the wall of the blood vessels. The infundibulum and the hypothalamus were markedly enlarged, tan, and granular in appearance.

TABLE 3 PERFORMANCE OF D.T. COMPARED TO NORMAL SUBJECTS AND PATIENTS WITH ALZHEIMER’S

DISEASE (RAW SCORES)

Alzheimer’s Normal Z scores’ disease subjects

(N = 20) (A’ = 20) D.T.* Alzheimer’s

Age 74.0 f 6.1 58.4 + 15.1 - - WAIS Block Design 3.4 f 5.8 29.0 f 10.3 -2.0 -2.5 WMS Orientation 3.7 2 1.1 5.0 + 0.2 +0.2 -5.8 WMS Current Information 2.4 + 1.6 5.7 2 0.6 -1.2 -5.4 Digits Forward 5.4 f 1.1 6.9 + 1.3 -2.2 -1.1 Digits Backward 2.4 f 1.1 4.5 f 1.4 -3.1 -1.5 WAIS Vocabulary 35.0 f 9.0 62.8 f 3.4 -1.4 -2.1 WMS Verbal Memory 2.9 f 2.4 9.4 2 3.1 -1.6 -2.1

a Number of standard deviations below the mean performance of normal subjects. b Based on test results of 7/12/82 (cf. Tables 1 and 2).


The blood vessels at the base of the brain appeared normal except for adhesions between the chiasm and the cranial nerves.

Serial coronal sections of the brain revealed an enlarged granular hypothalamus and infundibulum associated with enlargement and granularity of the columns of the fornix (Fig. 1 and 2). The white matter showed a few petechiae. No other grossly visible granulomata were identified else- where in the brain. The ventricles were of normal size.

Histologically, the fornix, the hypothalamus, and the infundibulum were replaced by noncaseating epithelioid granulomas associated with marked lymphocytic proliferation. Cultures and the special strains were negative for bacteria or fungi. Microscopic granulomas were present in the mesial temporal lobes, mammillary bodies, basal ganglia, and oc- casionally in the outer cortex. In addition, the meninges showed many perivascular granulomas especially at the base.

DISCUSSION

Albert (1978) has generated interest in the concept of subcortical dementia and has discussed the behavioral differences between cortical and subcortical dementia. However, it is difficult, if not impossible, to find demented subjects in whom pathological charges are confined wholly to the subcortical structures. As Victor (1978) has pointed out, neither Parkinson’s nor Huntington’s disease are examples of a pure subcortical disease. This case is of interest because the major lesions were confined to the hypothalamus and fornices. The cortex was largely spared except for a few microscopic granulomas in the temporal and frontal lobes. Microscopic-granulomas were also noted in the thalamus, putamen, and mammillary bodies. Thus, the sarcoid affected primarily subcortical structures with little involvement of the cerebral cortex. Analysis of his deficits provides another opportunity to elucidate the constellation of symptoms characterizing subcortical dementia.

D.T. did poorly on a number of psychometric measures including Verbal Memory (WMS), Visual Memory (WMS), Paired-Associate Learning (WMS), Digit Span (WMS), Block Designs (WAIS), and Picture Completion (WAIS). Thus he showed deficiencies in new learning ability, short-term memory, and visuospatial skills. The presence of visuospatial deficits extends his difficulties beyond purely memory deficits and suggests that his disorder should properly be called a dementia rather than an amnesia. Vocabulary, fund of information, and orientation were relatively spared.

It is of interest to contrast the memory difficulties of D.T. to subjects with amnestic syndromes due to hippocampal lesions (Woods, Schoene, & Kneisley, 1982; Warrington, 1971). Adopting the terminology of War- rington (1971), memory difficulties fall into three categories; short-term memory disorders (e.g. impaired digit span), anterograde amnesias (inability

SUBCORTICAL DEMENTIA

FIG. 2. Schematic drawing showing location of granulomas in fornix and hypothalamus (stippled areas).

to form new memories), and retrograde amnesias (inability to retrieve old memories). D.T. showed a striking short-term memory disorder as well as an anterograde amnesia with little retrograde amnesia. In contrast, most subjects with hippocampal amnestic syndrome show little evidence of a short-term memory disorder (normal digit span) and varying admixtures of anterograde and retrograde amnesia. Subjects with Alzheimer’s disease generally show a pattern of memory deficits similar to that of subjects with hippocampal amnesia (normal short-term memory contrasted with retrograde and anterograde amnesia).

When the performance of D.T. is compared to that of Alzheimer’s disease subjects several contrasts emerge. D.T. does better than the average Alzheimer’s disease subject on measures of Current Information and Orientation (WMS); he does less well than the average Alzheimer’s disease subject on immediate memory tasks (digits forward and backward). His performance was comparable to that of the average Alzheimer’s disease subject on the Block Design, Vocabulary, and Verbal Memory subtests (Table 3).

D.T.s preserved orientation despite poor new learning ability suggests


that orientation may not depend heavily upon the ability to efficiently form new memories. This observation is consistent with factor-analytic studies of the Wechsler Memory Scale (Skilbeck & Woods, 1980) that have showed that the Orientation and Current information subtests load on a factor that is distinct from a general learning factor (Paired Associates, Verbal Memory, and Visual Reproduction subtests). Similarly, Kim et al. (1982) have noted that orientation is often preserved in Huntington’s disease despite poor memory. In contrast, orientation is generally impaired early in Alzheimer’s disease (cf. Table 3).

Albert (1978) has outlined some features typical of the subcortical dementias including apathy, lack of spontaneity, prominent memory disorder, “slowness in the rate of information processing,” “inability to carry out complex integrative activities,” and “impaired ability to ma- nipulate acquired knowledge.” Consistent with the formulation of Albert, D.T. showed a considerable apathy and abulia as well as a marked disorder of memory. The prominent (and somewhat unusual) short-term memory disorder in D.T. has already been emphasized. Like patients with Huntington’s disease (Caine et al., 1977; Caine et al., 1978) D.T. has more difficulty with tests of new learning ability (e.g., the Visual Reproduction and Paired Associates tests of the WMS) as opposed to measures of fund of knowledge (e.g. Information and Vocabulary subtests of the WAIS). Furthermore, unlike most Alzheimer’s disease subjects, D.T. showed a preseveration of insight into his deficits. Kim et al. (1982) have described a similar preseveration of insight in Huntington’s disease.

The co-occurrence of a prominent memory deficit in D.T. and the lesion in the fornix (Fig. 1 and 2) is of interest. Memory loss has been reported in humans after lesions of the fornix (Sweet Talland, & Ervin, 1959; Hassler & Riechert, 1957). However, negative cases have also been reported (Woolsey & Nelson, 1975). Lesions situated in the fornix might be predicted to produce memory deficits since the fornix is the major efferent pathway connecting the hippocampus with the mammillary bodies, Bilateral destructive lesions of either the hippocampus or the mammillary bodies cause significant amnesia (Brion, 1969). Nonetheless, the amnesia of D.T. with his marked impairment of short-term memory differs dramatically from the amnesia of hippocampal injury which is characterized by intact short-term memory (Woods et al., 1982; Warrington, 1971).

The pattern of cognitive deficits in D.T. and those noted in Huntington’s disease subjects do appear to differ in important respects from the deficits characteristic of the so-called cortical dementias such as Alzheimer’s disease. The findings suggestive of a “subcortical” dementia include:

(i) better performance than most Alzheimer’s patients on measures of orientation, current information, and fund of knowledge;

(ii) comparable performance to Alzheimer’s patients on visuospatial and new learning measures;


(iii) inferior performance on measures of short-term memory (e.g., digit span);

(iv) relatively preserved insight into the illness; (v) apathy and abulia. These differences highlight the special importance of cortical structures

in maintaining insight, orientation, and fund of information and the special importance of subcortical structures to memory.

Note added in proof. C. Thompson and S. Checkley have recently reported (British Journal OfPsychiatry, 139, 160-161, 1981) a case of CNS sarcoidosis with a mild dementia (WAIS Full Scale IQ = 78) and prominent memory disturbance. A CT brain scan showed granulomatous involvement of the brain in the inferior frontal lobe. They conclude that “The limbic structures which are known to be involved in the acquisition of a short-term memory may have been damaged by the basal meningitis which is known to exist in cerebral sarcoidosis.”

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A case of subcortical dementia due to sarcoidosis of the hypothalamus and fornices

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