Case report

A 38-year-old male presented with a right-sided facial droop and hemiparesis following a 2-week prodrome of headache, fever, cough and right hemisensory symptoms. Soon after admission, he developed tonic–clonic seizures, necessitating treatment with phenytoin, intubation and ventilation. MRI revealed patchy signal changes in the thalamus, cerebellum, temporal and occipital lobes bilaterally, while MR angiogram revealed normal extra- and intracranial blood flow. Cerebrospinal fluid examination, vasculitic blood screen and transoesophageal echocardiogram were normal. Electroencephalography demonstrated features consistent with encephalopathy, and a diagnosis of ADEM was made. He subsequently received two courses of intravenous methylprednisolone, intravenous immunoglobulin, plasma exchange and antibiotics. He was also anticoagulated for a deep venous thrombosis and required surgical treatment for an associated compartment syndrome.

The patient remained in intensive care, due to persistent epileptiform activity, for 4 months, when seizures were stabilised on a regimen of levetiracetam 2 g, phenytoin 700 mg and prednisolone 30 mg. He was then transferred to a rehabilitation unit, at which time he had a tetraparesis, with predominant left-sided weakness.

Neuropsychological testing also revealed significant cognitive impairments, including left-sided neglect (with intact visual fields on confrontation), reduced arousal and difficulty sustaining attention. In addition, there were significant impairments in verbal memory (chance performance on the short and easy Recognition Memory Test for verbal material and low average performance on the Wechsler Adult Intelligence Scale—Revised (WAIS-R) Digit Span subtest) and naming (5/15 correct on Graded Naming Test). There was also evidence of dysfunction on tests of executive function (concrete performance on Proverb Interpretation and perseveration on Single Letter Reading and the Similarities subtest of the WAIS-R). On the basis of educational and occupational background, he was estimated to have been functioning in at least the superior range premorbidly and had therefore suffered severe intellectual deterioration.

Admission for reassessment occurred 2 years later, at which time anticonvulsant medication consisted of levetiracetam 750 mg and gabapentin 300 mg both twice daily (the total daily dose of levetiracetam was 1250 mg at 6 months' follow-up, with a further reduction to 1000 mg 10 months later). Cranial nerve examination was normal, except for a mild left-sided facial weakness. Examination of the limbs revealed a severe hemiparesis with increased tone on the left and a pyramidal distribution of weakness, worse distally. The limb reflexes were all brisk with bilaterally extensor plantar responses. There was severe left hemispatial neglect and impairments in sustained attention and arousal, with the patient spending 20 h a day in bed due to drowsiness. A decision was taken to trial the alpha-2-noradrenergic agonist guanfacine, with the hypothesis that this might improve these cognitive impairments.

Assessment measures

MRI was repeated to determine the extent of lesions (figure 1A). Two standard bedside neuropsychological tests were used to assess neglect, while a computerised task was used to measure the deficit in sustained attention. The neglect tests used were line cancellation, in which subjects are instructed to cancel all the lines they can find (total 40) distributed across an A4 sheet of paper and bisection of 17 cm horizontal lines, where the mean deviation rightwards from centre was taken from three attempts. The computerised task which has been used previously7 was presented on a Dell Latitude D820 laptop computer, and entailed the subject depressing the central button on a response box (RB-530 Cedrus Corp.), whenever an infrequently occurring black circle (8 mm diameter) occurred. The circle remained on the screen for 1 s and was presented on a grey background with interstimulus intervals of 1–7 s. 100 stimuli were presented over a total period of 8 min.

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Figure 1

Bilateral thalamic lesions associated with hemispatial neglect and impaired sustained attention, and amelioration with guanfacine. (A) Bilateral thalamic lesions as demonstrated by T2-weighted MRI scanning. The red arrow indicates one of the left-sided lesions, involving the medial thalamic nuclei, including the medio-dorsal nucleus. There are also smaller adjacent lesions in the pulvinar (blue arrow). The yellow arrow indicates the right-sided lesion, which is also in the pulvinar. (B) Line bisection. The rightward deviation on bisecting 17 cm lines decreased significantly after commencement of guanfacine (deviation given in mm). (C) Line cancellation. The total number of lines cancelled by the patient increased on 2 mg of guanfacine. (D) Perceptual sensitivity on the sustained attention task improved significantly on guanfacine treatment. Pre, preguanfacine; Post 1, initial assessment after commencement of 2 mg of guanfacine; Off, assessment at 2 months after guanfacine had been ceased for 2 weeks; Post 2, assessments at 6 months after initiation of guanfacine; Post 3, assessment at 16 months after initiation of guanfacine.

Responses quicker than 100 ms were classified as anticipations, and therefore as commission errors, as were responses occurring more than 1600 ms after target onset. Perceptual sensitivity, or d′, which is derived from signal detection theory8 and takes into account commission as well as omission errors, was the behavioural outcome measure of this task and calculated according to the formula below:d′=Φ−1(H)−Φ−1(F)where H is the hit rate, and F is the false alarm rate. The higher this value, the better the subject was at accurately detecting targets.

These tests were performed on two consecutive days prior to commencing guanfacine, as well as at several time points after its introduction. The dose of guanfacine was titrated up slowly over 3 days in the following increments: 0.5 mg, 1 mg and 2 mg as single daily doses. The first on-guanfacine testing session was performed the day 2 mg was reached.

An additional testing session off-guanfacine was performed 2 months later (due to initial difficulty obtaining the drug locally) at which point the patient had not received guanfacine for 2 weeks. Three on-guanfacine testing sessions were performed 6 months after the initial commencement of 2 mg of guanfacine daily, and a final session occurred a further 10 months later. Therefore, in total, the patient underwent three testing sessions off and five on guanfacine. Testing was always performed during the afternoon.

Guanfacine has previously been well tolerated in studies investigating its efficacy in children and adolescents with attention deficit/hyperactivity disorder; however, the most commonly experienced side effects include drowsiness, sedation and dizziness.5 9 The patient reported here did not experience any side effects.