Patients

The four patients who were transferred to Rennes University Hospital were previously healthy men, 27 to 49 years of age. No major clinical or surgical history and no history of drug abuse were reported at screening. They were taking no medication other than the study drug. At the time of the patients’ admission to the hospital, analyses for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates were negative. Two of the four patients had previously participated in phase 1 studies testing molecules that were not related to the endocannabinoid system.

Table 1. Table 1. Clinical Data for the Four Patients.

Table 2. Table 2. Description of Magnetic Resonance Imaging Abnormalities in the Four Patients.

The first day of drug administration (day 1) was January 6, 2016; clinical follow-up extended to 55 days. A 50-mg dose of BIA 10-2474 was administered orally to each patient between 8 a.m. and 8:45 a.m. each day; Patient 1 received the drug for 5 consecutive days, and Patients 2, 3, and 4 for 6 consecutive days. The first serious adverse event was reported on day 5. Clinical and radiologic data are summarized in Table 1 and Table 2.

Patient 1

At 11 a.m. on day 5, Patient 1 reported moderate blurred vision and floating specks. At 3:30 p.m., he reported moderate headache. When gait disturbance and slurred speech developed, he was transferred from the Biotrial clinical research facility to the emergency department of Rennes University Hospital at 8:50 p.m. The physician in the emergency department described moderate limb ataxia, which was worse on the left side, involving the arm and leg equally; moderate cerebellar dysarthria; and gaze-evoked and direction-changing nystagmus. The patient was awake and had no sensory loss, weakness, oculomotor paralysis, Babinski sign, reflex alteration, or memory defect. The temperature was 36.4°C, heart rate 62 beats per minute, blood pressure 149/89 mm Hg, and oxygen saturation 95% while the patient was breathing ambient air. A cranial computed tomographic (CT) scan and a CT angiogram were initially interpreted as normal. A subtle hypodensity in the pons could be seen, retrospectively. The complete blood count and blood levels of electrolytes, urea, creatinine, and C-reactive protein (CRP) were normal, as were the results of coagulation and liver-function tests. The patient received 160 mg of aspirin. At 7:45 a.m. on day 6, he suddenly became confused and agitated, and he had worse limb and postural ataxia with severe dysmetria, limb and truncal kinetic tremor, and an inability to sit up in bed.

Figure 1. Figure 1. Magnetic Resonance Imaging (MRI) Studies in Patient 1. Panels A through F depict MRI studies from day 6, and Panels G through K depict studies from day 8. On day 6, MRI showed hyperintense lesions (thin arrows) on diffusion-weighted images in the pons (diffuse lesion; Panel A) and right hippocampus (punctate lesion; Panel D), microhemorrhages (thick arrows) on susceptibility-weighted images in the pons (Panel B) and hippocampi (Panel E), and pathologic hypersignal (arrowhead) on fluid-attenuated inversion recovery (FLAIR) images in the pons (Panel C) and midbrain (Panel F). On day 8, MRI showed worsening of lesions: hyperintense lesions on diffusion-weighted images involving mainly the cortex, external capsula, thalami (Panel J) and the pons, hippocampi, amygdala, and mammillary bodies (not shown); microhemorrhages on susceptibility-weighted images in the hippocampi, amygdala, external capsula, all the basal ganglia, and the cortex (Panels G, H, and I); and pathologic hypersignal on FLAIR images in the cortex, thalami (Panel K), and the brain stem, hippocampi, and amygdala (not shown).

Magnetic resonance imaging (MRI) (Figure 1) showed hyperintensities in the pons and hippocampi on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted sequences, with multiple microhemorrhages in the pons. As the patient’s condition deteriorated further, he became unconscious (Glasgow Coma Scale score of 9, on a scale from 3 to 15, with lower scores indicating a reduced level of consciousness; the pupils were symmetric and reactive to light), and he required tracheal intubation and mechanical ventilation with sedation. The temperature became elevated to 38.2°C. The cerebrospinal fluid had 173 white cells per cubic millimeter (87% of which were neutrophils), a protein level of 353 mg per deciliter, and a glucose level of 4.58 mmol per liter; the serum glucose level was 8 mmol per liter (144 mg per deciliter). He received acyclovir, cefotaxime, and amoxicillin until cerebrospinal fluid studies for herpes simplex virus, varicella virus, and Listeria monocytogenes were determined to be negative. Levels of antinuclear antibodies, complement, and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) were normal, and there were no signs of thrombotic microangiopathy.

On day 7, the patient’s heart rate was slower than 40 beats per minute, and he was hypotensive. A CT scan showed edema of the brain stem, hippocampi, and temporal lobes. On day 8, he had bilateral dilated and light-unreactive pupils. MRI showed diffuse hyperintense lesions on FLAIR and diffusion-weighted sequences and multiple microhemorrhages, mainly involving the brain stem, hippocampi, cortex, and thalamus. He was declared brain dead the following day. An autopsy was performed, but the results have not been made available to the authors.

Patient 2

Figure 2. Figure 2. MRI Studies in Patient 2. A time series of diffusion-weighted images on day 7 (Panel A), day 8 (Panel B), and day 9 (Panel C) shows progressive worsening of hyperintense lesions in the hippocampi and amygdala. MRI on day 9 (Panels C through G) showed several moderate microhemorrhages (thick arrows) on susceptibility-weighted images in the median part of the pons (Panel D) and in the hippocampi and amygdala (Panel E) as well as pathologic hypersignal (arrowhead) on FLAIR images in the pons and anterior temporal lobe (Panel F) and in the hippocampi and amygdala (Panel G).

On day 7, Patient 2 began asking the same questions repeatedly about recent activities. He was transferred from the Biotrial clinical research facility to the emergency department of Rennes University Hospital. A neurologic examination was performed by the on-duty neurologist. The patient was incapable of encoding new facts, events, or names. Although the retrieval of information from years ago was relatively preserved, his memory for the previous 2 to 3 months was incomplete. He reported moderate headache. Brain MRI showed hippocampal and anterior pontine signal hyperintensities on diffusion-weighted sequences (Figure 2). The complete blood count and blood levels of electrolytes, urea, creatinine, and CRP were normal, as were the results of coagulation and liver-function tests.

On day 8, he had moderate dysarthria and moderate limb and gait ataxia (he was incapable of walking in a straight line). A second MRI scan showed hyperintense lesions on FLAIR and diffusion-weighted sequences and several microhemorrhages involving the pons and hippocampi. The patient received intravenous glucocorticoids from day 8 to day 12. On day 9, his condition was unchanged. A third MRI showed an increased number of microhemorrhages. His condition gradually improved, and at the last clinical follow-up, on day 55, his amnesic symptoms had lessened, but he had partial retrograde amnesia regarding the period from 2 months before to 1 month after administration of the drug and minimal anterograde amnesia. Dysarthria and ataxia were no longer evident. MRI showed that the diffusion-weighted hyperintensities had disappeared and that the FLAIR hyperintensities had partially regressed (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The hippocampi had heterogeneous signal hyperintensities, and some focal hyperintensities were still visible in the pons on FLAIR images. No new lesion had appeared.

Patient 3

Figure 3. Figure 3. MRI Studies in Patient 3. MRI on day 8 showed hyperintense lesions (thin arrows) on diffusion-weighted images in the pons (Panel A), several microhemorrhages (thick arrows) on susceptibility-weighted images in the median pons (Panel B), and pathologic hypersignal (arrowhead) on FLAIR images in the pons (Panel C) and hippocampi (Panel D). MRI on day 9 showed punctate hyperintense lesions (thin arrows) on diffusion-weighted images in the hippocampi and amygdala (Panel E), worsening of existing microhemorrhages (thick arrows) on susceptibility-weighted images in the median pons (Panel F) as well as new microhemorrhages in the hippocampi and amygdala (Panel G), and pathologic hypersignal (arrowhead) on FLAIR images (Panel H) in the pons, anterior part of the medulla oblongata, and the hippocampi (not shown).

On day 5, Patient 3 reported mild asthenia, headache, and dizziness, but repeated neurologic examinations performed by the physician at the Biotrial clinical research facility were normal. At 7:38 a.m. on day 8, he presented with a subacute gait disturbance, slurred speech, and a syncope. He was transferred from the Biotrial facility to the emergency department of Rennes University Hospital. A neurologic examination was performed by the on-duty neurologist. The patient was somnolent and had severe limb, gait, and postural ataxia (he was unable to walk or sit up in bed without assistance) and moderate dysarthria. No sensory or motor disturbances (including oculomotor paralysis) and no memory defects were found. Nystagmus (gaze-evoked and direction-changing) subsequently appeared. The headache ceased. The results of blood tests were normal. MRI showed hyperintensities on diffusion-weighted and FLAIR sequences in the brain stem (pons and medulla oblongata) and hippocampi and a focal microhemorrhage in the pons (Figure 3). The cerebrospinal fluid had a protein level of 1.13 g per liter but no white or red cells. He received intravenous glucocorticoids from day 8 to day 10. On day 9, the cerebellar syndrome was unchanged. On day 10, he had severe dysarthria and somnolence. He was given 1 g of intravenous cyclophosphamide.

His condition gradually improved beginning on day 11, and he could walk without assistance on day 13. At the last clinical follow-up on day 55, he was able to walk without assistance but had difficulty with tandem gait and had nystagmus on left lateral gaze. MRI showed that the diffusion-weighted and FLAIR hyperintensities in the medulla oblongata and hippocampi had disappeared (Fig. S2 in the Supplementary Appendix). Focal hyperintensities were still visible in the pons on FLAIR images, as were microhemorrhages.

Patient 4

Patient 4 had moderate diarrhea on days 6 and 7. MRI scans on days 8 and 10 were normal, except for an asymptomatic cavernous malformation located in the brain stem. On day 55, he remained asymptomatic.