Cognitive Loss in Multiple Sclerosis Case Reports and Review of the Literature Gary M. Franklin, MD, MPH; Lorene M. Nelson, MS; Christopher M. Filley, MD; Robert K. Heaton, PhD \s=b\ Neuropsychological and neuroradiologic evidence of cerebral lesions is described for 12 patients with multiple sclerosis in whom cognitive disability was far greater than any other neurologic disability. Cognitive dysfunction resulted in significant functional impairment at work or home in three fourths (9 of 12) of the patients described here, despite mild physical disability (mean Kurtzke Expanded Disability Status Scale score, 3.2). A unique feature of the neurologic examination in these patients was the presence of prominent frontal release signs (gait apraxia and placing response) in the lower extremities. Two new scales, a Cognitive Function Scale and a Frontal Release Scale, were adapted for the investigation of these patients. The extensive literature relating to cognitive dysfunction in multiple sclerosis is reviewed and discussed with regard to its clinical relevance. (Arch Neurol 1989;46:162-167) "Decent studies13 have clearly demon¬ strated that neuropsychological deficits in patients with multiple scle¬ rosis (MS) are more frequent than has been generally recognized. Several facts may account for the prior lack of awareness that functionally impor¬ tant cognitive disturbance can occur in MS as a significant and sometimes predominant problem. First, the degree of cognitive impairment is not significantly related to the degree of neurologic disability.1·4 Second, pa¬ tients with predominant periventric¬ ular demyelination, even with long¬ standing disease, may be considered See also mildly affected 157. or "silent" with respect to neurobehavioral deficits.5 Third, the bedside mental status examination normally performed by neurologists may not detect cognitive impairment in persons with MS.1·2 We have recently seen 12 patients at our center whose cognitive deficits were far more disabling than any other of their MS-related neurologic impair¬ ments. This report briefly describes seven illustrative cases, summarizes the findings in the entire group, and reviews the literature relevant to these findings. PATIENTS AND METHODS Accepted for publication Oct 10, 1988. From the Rocky Mountain Multiple Sclerosis Center (Dr Franklin and Ms Nelson) and the Departments of Neurology (Drs Franklin and Filley), Preventive Medicine and Biometrics (Dr Franklin), and Psychiatry (Drs Filley and Heaton), University of Colorado School of Medicine, Denver. Dr Franklin is now at the Department of Environmental Health, University of Washington School of Public Health and Community Medicine, Seattle. Dr Heaton is now at the Department of Psychiatry, University of California, San Diego. Reprint requests to the Department of Environmental Health, SC-34, University of Washington School of Public Health and Community Medicine, Seattle, WA 98195 (Dr Franklin). Patients were tested individually by trained neuropsychological technicians with one of two standardized test bat¬ teries: an eight-hour expanded HalsteadReitan Battery (HRB) or our one-hour Neuropsychological Screening Battery (NSB). A brief overview of these test bat¬ teries is presented below. Detailed descrip¬ tions of the specific tests and abilities assessed are given elsewhere.1·6 The expanded HRB is a comprehensive, standardized test battery with demon¬ strated sensitivity to focal and diffuse cerebral lesions.7 It assesses the following abilities: problem-solving, attention/con- Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/14/2015 centration, learning and delayed recall (verbal and nonverbal), intelligence, aca¬ demic skills, concept formation, persevera¬ ron, perceptual motor speed, visuospatial abilities, sequencing efficiency, sensoryperceptual functions, expressive and recep¬ tive language, and motor proficiency. To minimize practice effects, alternate forms of the learning/memory tests were used whenever patients were tested more than once. The NSB is a briefer set of standardized cognitive tests that were combined in an attempt to provide greater sensitivity to cognitive deficits than clinical mental sta¬ tus examinations.6 The NSB also has dem¬ onstrated superiority to two widely used standardized mental status examination (the Mini-Mental State examination and the Cognitive Capacity Screening Exami¬ nation) in the detection of cognitive defi¬ cits in MS.6 In addition, the NSB summary score was significantly correlated with the extent of white-matter involvement seen with magnetic resonance imaging (MRI).6 The NSB consists of 18 subtests that assess the following abilities: verbal learning and memory, nonverbal learning and memory, attention/concentration, visuoconstructional abilities, sequencing efficiency, psychomotor speed, expressive and receptive language, speech articulation, written flu¬ ency, and reading comprehension. Stan¬ dard cutoff values6 for normal, mildly impaired, and very impaired were used to classify the degree of cognitive impairment on the NSB subtests and NSB summary score. The Kurtzke Expanded Disability Status Scale (EDSS)8 was used as a measure of physical disability; brain-stem, cerebellar, and pyramidal deficits are heavily weight¬ ed in this scale. By contrast, two of the major clinical problems encountered in this series, cognitive impairment and low¬ er-extremity frontal release signs, are poorly represented or not represented, respectively, by the EDSS. Two scales were developed to enable functional classifica¬ tion of these clinical problems (Tables 1 and 2). The Cognitive Function Scale (Table 1) is descriptive method to grade the degree of impairment of activities of daily living (particularly employment) related to clini¬ cal cognitive dysfunction. The cases described below are organized (Table 3) according to this method of grading the functional impact of neurocognitive im¬ pairment. Similarly, the Frontal Lobe Release Sign Scale is purely a descriptive method to grade the degree of lowerextremity frontal release. In the course of our clinical observation, for example, it was clear that mild placing or grasping in the feet is a less severe sign than gait apraxia. This scale, then, reflects this gra¬ dation of lower-extremity frontal release. Both scales were developed for descriptive purposes only; further reliability and validity studies should be done if these scales are applied in studies other than a Table 1.—Cognitive Function Scale Table 2.—Frontal Lobe Release Signs Grade_Description Grade Description 0 No signs Mild lower-extremity placing without Normal function Mild alteration of 0 1 continues to work or function unable to work due Repeated neuropsychological testing at Severe gait apraxia; may require aids apraxia to cognitive impairment Severe alteration of 3 living pattern; unable to function independently Table 3.—Demographic and Clinical Summary of Patients (N Disease Patient No./ Duration, Age, y/Sex y 2/27/F scribed. A 30-year-old woman presented to our center in January 1984 with a three-month history of dizziness and forgetfulness. Although she had been diagnosed with MS in 1983, she had experienced relapsing/ remitting symptoms since 1980. Her neuro¬ logic examination disclosed poor recent memory and mild left-sided pyramidal dysfunction. The Kurtzke EDSS score was 3.5 (Table 3). A computed tomographic (CT) scan (Fig 1, top left) revealed multiple periventricular lesions, at least three of which appeared acute (ie, contrast enhanc¬ this time revealed improved concept for¬ mation but continued severe memory impairment. By October 1984, the patient reported increased difficulty with cogni¬ tion in her work as a secretary. An MRI scan disclosed moderately severe periven¬ tricular demyelination (Fig 1, top center), as well as multiple corpus callosum lesions (Fig 1, top right). Because of complaints of progressive cognitive difficulty, the pa¬ tient was admitted to the hospital for cyclophosphamide therapy.' The patient has subsequently had three cyclophospha¬ mide boosts (700 mg/m2) in the one year following initial treatment. No dramatic 3 living pattern; gression of cognitive symptoms responding to cyclophosphamide therapy is de¬ and nonverbal material. Because of lack of response to steroid therapy, the patient was treated with azathioprine for the ensuing six-month period. During this time, she reported fewer memory difficul¬ ties. A repeated CT scan in August 1984 revealed that some previously seen lesions had disappeared, but that new lesions had appeared. Azathioprine therapy was dis¬ continued because of hepatic dysfunction. Clear lower-extremity placing with mild to moderate gait independently Case 1.—Acute exacerbation and pro¬ ing). Comprehensive neuropsychological testing with the HRB revealed a Wechsler Adult Intelligence Scale Full-Scale intelli¬ gence quotient of 94 and an HRB summary score in the mildly impaired range. Howev¬ er, she also showed severely impaired learning and delayed recall of both verbal gait apraxia 2 Moderate alteration of 2 case series. REPORT OF CASES Cognitive Function Grade 1 (Table 1) 1 living pattern; 4 Frontal Release EDSS Disease Score Grade Course Cognitive Function Grade 1 R/R 3.5 0 = 12)* Kurtzke 2.5 0 Neuropsychologlc Deficitf VL, VM, NVL, NVM CPS, NVAP R/R NVM R/R NVL, NVM, AC, VSA, LA Cognitive Function Grade 2 4/42/F 20 3.5 2 R/R VM, NVM, CPS, AC, 5/33/M 8/46/F 1 3.5 1 R/R 12 3,0 2 R/R 9/48/F 11 2.5 2 R/R 10/37/F 5 3.5 2 C/P 11/45/F 22 4.0 2 C/P NVM, AC, VSA, LA VL, VM, NVL, NVM, CPS, AC, LA VL, NVL, NVM, AC, VSA, LA VL, VM, NVL, NVM, AC, VSA, LA CPS, AC VL, NVL, AC, LA 6/31/F 4 3.5 3 C/P 7/45/F 5 5.0 3 C/P 8.3 3.2 NVAP Cognitive Function Grade 3 VL, NVL, CPS, AC, VSA, NVAP, LA VL, VM, CPS, AC, LA Mean ./38.6/. . . . . *EDSS indicates Expanded Disability Status Scale; R/R, relapsing/remitting; C/P, chronic/progressive; VL, verbal learning; VM, verbal memory; NVL, nonverbal learning; NVM, nonverbal memory; CPS, complex problem-solving; NVAP, nonverbal auditory processing; AC, attention/concentration; VSA, visuospatial ability; and LA, language ability. tAII deficits were moderate to severe. worsening of cognitive function has occurred and her current Kurtzke EDSS score is 2.5. She continues to work full time. Case 2.—Cognitive deficits presenting acutely, with subsequent full remission, are described. A 27-year-old woman presented with a six-week history of cognitive disorganiza¬ tion and poor recall of recent events. These symptoms were noticed quite acutely. She had experienced relapsing/remitting MS symptoms for four years. Results of her neurologic examination, including bedside cognitive testing, were normal except for minor sensory deficits (EDSS score, 2.5). An expanded HRB revealed a moderately severe, isolated deficit in nonverbal memo¬ ry. Results of a CT scan done at this time Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/14/2015 patient's cognitive com¬ plaints completely abated three months after they began. Results of a repeated HRB at this time were entirely normal. Case 3.—Coexistent depression and were normal. The memory loss are described. A 30-year-old woman had relapsing/ remitting MS for six years prior to treat¬ ment at our center. She presented with a chief complaint of intermittent depression and recent memory loss. The depression had been refractory to intensive psycho¬ therapy and antidepressant medication. Her neurologic examination revealed a Kurtzke EDSS score of 1.5. She also exhib¬ ited mild lower-extremity frontal release signs. The NSB revealed moderate to severe impairment in memory, attention/ concentration, visuospatial ability, and language ability. An MRI scan disclosed multiple periventricular lesions with mod¬ erate supratentorial atrophy (Fig 1, bot¬ tom left) as well as both rostral (Fig 1, bottom center) and caudal (Fig 1, bottom right) corpus callosum lesions. It is of note that this patient had been examined by a number of community physicians and ther¬ apists, all of whom recognized the depres¬ sion, but not the cognitive difficulties. Cognitive Function Grade 2 Case 4.—Cognitive dysfunction after a long history of benign illness is de¬ scribed. A 42-year-old woman presented to our center with a 24-year history of relapsing/ remitting MS. Her history included bouts of right-leg clumsiness and diplopia. She presented with a two-year history of mem¬ ory complaints and increasing difficulty in her work as a teacher. Neurologic exami¬ nation revealed poor recall, impaired cal¬ culation ability, moderate gait apraxia, and a clear lower-extremity placing response. The Kurtzke EDSS score was 3.5. The NSB revealed moderate to severe impairment in verbal memory, sequencing efficiency, attention and concentration, and psychomotor speed. An MRI scan revealed extensive and confluent periven¬ tricular white-matter disease with mild ventriculomegaly and diffuse supratento¬ rial volume loss (Fig 2, top left and center). Also noted was a linear increase in signal intensity along the length of the corpus callosum (Fig 2, top right). Soon after her visit to our center, the patient was granted Social Security disability compensation based on cognitive dysfunction from MS. Fig 1.—Top, Patient 1. Acute, contrast-enhancing lesions can be seen on computed tomographic (top left). Moderate periventricular demyelination (top center), and multiple corpus callosum lesions (top right) are seen on magnetic resonance imaging. Bottom, Patient 3. Magnetic resonance imaging reveals extensive periventricular demyelination (bottom left), extremely thin rostral corpus callosum (bottom center), and demyelination in posterior corpus callosum (bottom scan right). Case 5.—Cognitive dysfunction coexis¬ tent with bipolar disorder is described. A 33-year-old man with a one-year his¬ tory of relapsing/remitting MS presented to our center with a one-week history of fatigue and left-sided incoordination. His symptoms improved significantly after a two-week course of oral prednisone. The patient was seen again six months later, when he presented with a one-month histo¬ ry of severe memory complaints and man¬ ic-depressive behavior. He had recently lost his job because of thinking difficulties and aberrant behavior. Neurologic exami¬ nation disclosed prominent memory loss, mild pyramidal and cerebellar signs, mod¬ erate lower-extremity placing, and gait apraxia. The Kurtzke EDSS score was 4.0. The NSB revealed moderate to severe impairment in nonverbal memory, se¬ quencing efficiency, attention and concen¬ tration, and psychomotor speed. An MRI scan revealed multiple periventricular lesions with severe periventricular volume loss (Fig 2, bottom left) and isolated callosal lesions (Fig 2, bottom center and right). The patient's memory impairment on repeated NSB and clinical examinations improved after high-dose intravenous ste¬ roid therapy. His behavioral disorganiza¬ tion has remained stable with mainte¬ nance haloperidol therapy (0.5 mg twice each day). He continues to demonstrate cognitive dysfunction that precludes em¬ ployment. Fig 2.—Top, Patient 4. Magnetic resonance imaging reveals confluent periventricular demyelin¬ ation (top left), ventricular enlargement (top center), and linear increase in signal intensity in corpus callosum (top right). Bottom, Patient 5. Magnetic resonance imaging reveals periventri¬ cular volume loss (bottom left) and isolated callosal lesion (bottom center) in normally thick corpus callosum (bottom right). Cognitive Function Grade 3 Case 6.—Isolated cognitive dysfunction with gait apraxia is described. A 31-year-old woman presented to our center with a four-year history of MS. Her primary complaint was progressive gait difficulty during the preceding two years. She had recently quit her job as an admin- Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/14/2015 istrative assistant in a physician's office. The patient had been told that her prob¬ lems were related to depression. Bedside mental status examination revealed poor concentration, abstraction, and calcula¬ tions. She exhibited a severely apraxic gait with placing response. Other neurologic dysfunction was minimal. Her Kurtzke EDSS score was 3.5. A CT scan revealed and one (patient 7) received only bed¬ side mental status testing. The neu¬ ropsychological results are summa¬ rized in Table 3. The subtest results can be clinically related to the follow¬ ing broad cognitive abilities: verbal and nonverbal learning and memory, complex problem-solving ability, at¬ tention and concentration, visuospatial ability, nonverbal auditory pro¬ cessing, and language abilities. NEURORADIOLOGIC FINDINGS Ten of the 12 patients had MRI scans. All scans revealed moderate to severe periventricular disease, includ¬ ing confluent lesions. Ventriculomegaly was noted in ten patients, and three patients had specific corpus cal¬ losum lesions or callosal atrophy. COMMENT extensive literature Although prior to 1980 documents cognitive dys¬ function in MS,1014 major recent an Fig 3.—Top, Patient 6. White-matter attenuation with ventricular enlargement on computed tomographic scan (top left) compared with confluent periventricular demyelination on magnetic resonance imaging (top center) and normal 48-hour cisternogram (top right). Bottom, Patient 7. Computed tomographic scan reveals marked frontal atrophy, ventricular enlargement, whitematter attenuation, and diffuse sulcal enlargement. diffuse white-matter attenuation and ven¬ tricular enlargement (Fig 3, top left). An MRI scan showed confluent demyelination (Fig 3, top center). The expanded HRB disclosed severe impairment across a wide range of functions (especially recent mem¬ ory) and, in this college graduate, a Wechsler Adult Intelligence Scale FullScale intelligence quotient of 82. The patient's cognitive symptoms have contin¬ ued to deteriorate over the ensuing 1.5 years. Her gait apraxia is now severe enough to require bilateral assistance. A recent isotope cisternogram revealed no evidence of spinal fluid flow disturbance (Fig 3, top right). Case 7.—Global dementia and severe gait apraxia are described. A 45-year-old woman presented to our center in 1985 with progressive gait disor¬ der and difficulty handling her personal and business affairs. Although the diagno¬ sis of MS had been made in 1980, she was noted to have optic atrophy even at that time. Neurologic examination disclosed global dementia and severe gait apraxia. Other neurologic functions, except visual acuity, were minimally impaired. Her Kurtzke EDSS score was 5.0. A CT scan revealed severe white-matter attenuation, diffuse cortical atrophy, and modest ven- triculomegaly (Fig 3, bottom). SUMMARY OF PATIENTS Table 3 contains a demographic and clinical summary of the patients. The mean age of the patients (N 12) was 38.6 years. Disease duration = was five years or less in six patients, six to ten years in two patients, and more than ten years in four patients. Only four of these 12 patients would have been considered to have a chron¬ ic/progressive disease course, the rest having relapsing/remitting histories. The mean Kurtzke EDSS score for the group was only 3.2. The mean number of functional systems involved was 6.2 (maximum number possible is eight). Except for cerebral dysfunction, no predilection for severe involvement in specific systems was noted. All but two of these patients had frontal lobe release signs seen pre¬ dominantly in the lower, but not the upper, extremities. Seven of 12 patients had moderate gait apraxia, and two of the 12 had gait apraxia enough to eventually require walking aids. All but two patients had a placing response in the feet. This flexor response to plantar stimulation was strong enough in six patients to severe the Babinski response, overcome which could only be elicited by stimu¬ lating the lateral side of the foot. Only the most severely impaired patient (patient 7) exhibited any frontal release signs in the upper extremi¬ ties. NEUROPSYCHOLOGICAL FINDINGS Five of the 12 patients received the expanded HRB, six received the NSB, Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/14/2015 reviews of MS15-16 have not focused on this aspect of the disorder. Popula¬ tion-based studies, using a brief bed¬ side mental status examination, have suggested that significant cognitive dysfunction may occur soon after onset in 2.0% to 2.9%17·18 or after 17 " years in as many as 25% of patients. More recent applications of standard¬ ized neuropsychological test batteries have demonstrated cognitive dysfunc¬ tion in 46%' of patients with relaps¬ ing/remitting courses and in 63%3 to 72%' of patients with chronic/pro¬ gressive courses. It is clear that more rigorous neuropsychological investi¬ gations yield higher rates of cognitive dysfunction. There has been, to date, little information on the neurologic and functional relevance of these find¬ ings. The patients presented here were striking to our clinicians in a number of ways: 1. Their functional cognitive im¬ pairment was far worse than any oth¬ er neurologic impairment. 2. Nearly all of the patients had evidence of frontal lobe release signs in the lower extremities. 3. The extent of cognitive impair¬ ment was unrelated to neurologic dis¬ ability status, disease course, or dis¬ ease duration. 4. Our routine bedside mental sta¬ tus examination could not predict the range and extent of cognitive impair¬ ment except in the most severely impaired patients. 5. Cognitive dysfunction, like any other neurologic deficit in MS, can present acutely, subacutely, or chroni¬ cally. 6. Affective disturbance may her¬ ald the presence of cognitive dysfunc¬ tion. 7. Most of the patients had been followed up for months to years with their cognitive impairment undiscov¬ ered. Although the mean EDSS score was only 3.2 in these patients, two thirds of them experienced cognitive impair¬ severe enough to preclude employment. In contrast to cognitive function, all other functional systems were mildly impaired. The mean num¬ ment ber of functional systems involved (6.2), however, suggests widespread, albeit mild, disease. Neither cognitive dysfunction nor frontal release signs in the lower extremities are adequately repre¬ sented in the Kurtzke scale, which is heavily weighted for brain-stem, cerebellar, and spinal cord dysfunction. Formal psychometric studies1·4 have found no correlation between degree of cognitive impairment and the EDSS score. The number of lesions on cranial MRI has low correlation with specific neurologic dysfunction," and the degree of cranial lesion burden by MRI does not correlate with the EDSS score even in patients with chronic/ progressive courses.6 The addition of both cognitive function and frontal release/apraxia components to future scales may permit demonstration of more salient relationships between brain lesions and neurobehavioral deficits. Except for occasional case reports,20 neither the frontal release signs nor the apraxia, both predominant in the lower extremities, has been previously described in MS. The degree of func¬ tional cognitive disability (Table 1) was highly correlated (Spearman's r .90; < .001) with the degree of frontal release/apraxia (Table 2) in the 12 patients described here. The predominance of the frontal release signs and apraxia in the lower extremities in MS is similar to the pattern seen in patients with normalpressure hydrocephalus.21 Neuroanatomic correlation may be related to the periventricular demyelination seen in both disorders. Although recent reports have suggested abnor¬ mal cisternogram patterns in patients with MS,22·23 one of our most severely affected patients (patient 6) had a completely normal isotope cisterno¬ gram (Fig 3, top right). It seems that periventricular demyelination, rather than an abnormality of spinal fluid flow, accounts for the similarity on CT in these two disorders. Fifty percent (six of 12) of our = patients developed serious cognitive dysfunction within five years of dis¬ ease onset, including the two most severely disabled patients. Prior reports have suggested that severe, early cognitive loss can occur in MS.24'26 More recent studies using psy¬ chometric test batteries have also found that cognitive dysfunction can occur early in a disease course2'4-27 or in the presence of mild physical disabili¬ ty.28 Mild to moderate impairment of visual and verbal memory was noted in 60% of patients who presented with MS duration of less than two years or optic neuritis alone.4 These findings may correlate with the presence of periventricular demyelination, which occurs in 50% of patients presenting with idiopathic optic neuritis.29 Even among our six patients whose disease duration was more than five years (range, six to 20 years), four were considered to have relapsing/ remitting disease. These patients all had evidence of moderate to severe periventricular white-matter disease on CT or MRI scan in spite of a mean EDSS score of only 2.8. Significant cognitive dysfunction may, therefore, long disease dura¬ tion who otherwise appear benignly affected. These findings also suggest that subtle cognitive dysfunction may have been overlooked in patients with occur in those with "silent" lesions5 discovered at post¬ mortem examination. Disease duration in this descriptive study had no correlation with degree of cognitive functional impairment. These patients, however, were se¬ lected for early or prominent cogni¬ tive impairment. In 100 unselected outpatients with MS, the correlation between cognitive impairment and disease duration was significant but low (r .22; < .05).' This same level < .04) has of correlation (r .25; recently been described between extent of MRI abnormality and dis¬ ease duration.30 These weak but statis¬ tically significant correlations sug¬ gest that, although important, disease duration is not an accurate predictor of either cognitive dysfunction or = = severe periventricular demyelination in an individual patient. The nature of the cognitive dysfunc¬ tion in MS has recently been exten¬ sively reviewed.31 It is clear both from the results of neuropsychological test¬ ing in our cases (Table 3), as well as from the application of a comprehen¬ sive psychometric battery in a consec¬ utive series of referral center pa¬ tients,1 that the range of cognitive deficits in MS is broad. Specifically, however, the kinds of deficits in mem- Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/14/2015 ory and language skills that would normally bring a patient with demen¬ tia to the attention of family or physi¬ cian are less marked than those seen in the dementia of Alzheimer's dis¬ ease.32 By contrast, disorders of atten¬ tion32 and difficulties with problemsolving and concept formation1·2 may be relatively more severe. Such defi¬ cits are not usually apparent in casual interactions, and may only be noticed in everyday situations that require patients to perform detailed or novel tasks. This subtlety of cognitive impairment would help explain the lag time in discovering the functional¬ ly significant cognitive dysfunction in some of the cases reported here. The structural correlates of the cog¬ nitive changes in MS are not entirely clear. Both increased ventricular size33·34 and atrophy of the corpus cal¬ losum35 have been correlated with cog¬ nitive impairment. The degree of peri¬ ventricular demyelination has also been significantly correlated with the extent of cognitive impairment.6 Cor¬ tical-subcortical or cortical-cortical disconnection, resulting from focal or diffuse periventricular and callosal demyelination, may be the best cur¬ rent explanation for the cognitive def¬ icits in MS.32 It is clear that cognitive dysfunc¬ tion, like other neurologic deficits in MS, may occur with relapse and remission (patient 2), relapse and pro¬ gression (patients 1 and 5), or chronic progression (patients 6 and 7). The CT and psychometric evidence of an acute cognitive relapse with complete clear¬ ing in patient 2 has not been previous¬ ly reported. Patient 1, with relapsing/ progressive cognitive deficits, has been stabilized by cyclophosphamide therapy9 and remains at work. Evi¬ dence for progression of cognitive def¬ icits in MS has been suggested previ¬ ously.10 Affective disorder heralded the cog¬ nitive dysfunction in two of our cases. Patient 3 was brought to our attention with subacute depressive symptoms that were refractory to counseling. Patient 5 presented with concomitant manic-depressive psychosis and cog¬ nitive dysfunction. Recent attention to affective disorders in MS has dem¬ onstrated that patients with MS with cerebral involvement have more depressive episodes than those with noncerebral involvement,34·36 depres¬ sion is more common in MS than in amyotrophic lateral sclerosis or tem¬ poral lobe epilepsy,37 and MS may present with depressive disorder prior to diagnosis.38 The association of a rapidly cycling bipolar illness with MS has also been recently reported.39 These findings suggest that affective disorder may be an organic concomi¬ tant of MS, possibly related to cogni¬ tive dysfunction as well as to specific patterns of subcortical demyelin¬ ation.34 Serious loss of cognitive function should be considered in patients with MS who (1) have chronic/progressive disease; (2) have demonstrated frontal release signs or apraxia, both promi¬ nent in the lower extremities; (3) present with depression or bipolar disorder refractory to treatment; (4) complain of cognitive difficulties at work or home, particularly in the areas of memory, attention, or com¬ plex problem-solving skills; and (5) have moderate to severe periventricu¬ lar abnormality on MRI scan, even early in the disease course in the absence of progressive neurologic def¬ icit. In cases of suspected cognitive loss, the use of a brief neuropsycho¬ logical screening battery,6 possibly adding tests of concept formation,2 would be appropriate. Such a battery, more sensitive to subtle cognitive def¬ icit than either the bedside mental status examination1·2 or the Folstein Mini-Mental State examination,6 can be used for screening, clinical trial monitoring, or clinical documentation of the progress of cognitive dysfunc¬ tion over time. A more detailed, exten¬ sive neuropsychological battery1 might be important in determination of vocational disability due to cogni¬ tive dysfunction and in other situa¬ tions that require a comprehensive assessment of cognitive strengths and deficits. This might prove to be impor¬ tant in applying recently devised methods of cognitive rehabilitation40 to those with cognitive deficits and MS. Finally, the application of both traditional and experimental thera¬ pies in MS should be done with consid¬ eration for cognitive dysfunction as a potentially critical factor in the total¬ ity of MS disability. This study was supported in part by the Gen¬ eral Clinical Research Center (National Insti¬ tutes of Health RR00051). References 1. Heaton RK, Nelson LM, Thompson DS, et al: Neuropsychological findings in relapsing/remitting and chronic/progressive multiple sclerosis. J Consult Clin Psychol 1985;53:103-110. 2. Peyser JM, Edwards KR, Poser CM, et al: Cognitive function in patients with multiple scle- rosis. Arch Neurol 1980;37:577-579. 3. Rao SM, Hammeke TA, McQuillen MP, et al: Memory disturbance in chronic/progressive multiple sclerosis. Arch Neurol 1984;41:625-631. 4. Lyon-Caen 0, Jouvent R, Hauser S, et al: Cognitive function in recent onset demyelinating diseases. Arch Neurol 1986;43:1138-1141. 5. Gilbert JJ, Sadler M: Unsuspected multiple sclerosis. 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