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Thrombotic thrombocytopenic purpura (TTP) is an ischemic vasculopathy frequently associated with neurological dysfunction including seizures. However, status epilepticus (SE) has rarely been reported in this condition. We report on a 70-year-old woman with fulminant TTP who developed convulsive SE despite high therapeutic serum levels of phenytoin and phenobarbital. Her electroencephalogram (EEG) was characterized by bilateral independent periodic lateralizing epileptiform discharges (BIPLEDs) propagating into clinical and electrographic seizures. She recovered completely after intensive plasmapheresis and treatment with pentobarbital induced coma for 5 days. This case illustrates that aggressive treatment with pentobarbital and plasmapheresis may prevent permanent neurologic deficits when TTP is complicated by SE and that periodic lateralizing epileptiform discharges (PLEDs) in this syndrome can be the manifestation of a reversible ischemic insult.
Thrombotic thrombocytopenic purpura (TTP) is a rare syndrome of unknown etiology characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological abnormalities, renal impairment and fever. In its fulminant form, diffuse thrombotic lesions in the central nervous system cause seizures and coma.
Since the introduction of plasma infusions and exchanges, the prognosis of the disease has improved dramatically; remissions now occur in 80–90% of patients.
Neurologic symptoms and signs are amongst the most common presentation of TTP, including alteration in the level of awareness, waxing and waning neurological deficits, headaches and coma.
We describe an elderly woman with TTP who developed convulsive SE during her illness associated with bilateral independent periodic lateralizing epileptiform discharges (BIPLEDs) on EEG. She completely recovered and the electroencephalogram (EEG) normalized following treatment with pentobarbital-induced coma and intensive plasmapheresis.
Case report
A 70-year-old woman with a history of diverticulitis and peptic ulcer was admitted to a community hospital because of abdominal pain and bloody diarrhea. Her platelet count was 53,000 mm−3 and creatinine level was 210 μmol/l. One week earlier, her platelet count was 290,000 mm−3. Brain computed tomography (CT) and cerebrospinal fluid examination were normal. Two days after admission, she was transferred to the University of Michigan Medical Center because of progressive confusion and focal motor seizures. On admission, her temperature was 100.2 °F, blood pressure 120/72 mmHg, and pulse rate 82 min−1. She was lethargic, disoriented to time, and complained of abdominal and back pain. She was unable to look past midline on attempted left lateral gaze and her left plantar response was equivocal. Physical examination was otherwise unremarkable.
Laboratory results revealed hemoglobin 10.8 g/dl, hematocrit 27.7%, white blood cell count 9100 mm−3, platelet count 27,000 mm−3, creatinine 270 μmol/l, LDH 1326 IU/l (normal 60–200), fibrinogen 2.7 g/l (normal 1.5–3.5), erythrocyte sedimentation rate 15 mm/h (normal 0–20), prothrombin time 13.4 s, partial thromboplastin time 22 s and reticulocyte count 2.9% (normal 0.5–1.5). A peripheral blood smear revealed moderate numbers of schistocytes and few helmet cells. Bone marrow aspiration and biopsy showed an increased number of megakaryocytes.
Treatment for TTP began immediately with plasma infusions. The following day, her mental status was normal, but during the next few days, despite a decrease in serum creatinine levels, she was intermittently confused. Three days after admission, the patient experienced a single generalized tonic-clonic (GTC) seizure for which she received an intravenous loading dose of phenytoin. Repeat brain CT was normal except for a small low density lesion in the hypothalamus. She was started on daily plasmapheresis for 3 days. Six days after admission, she was found stuporous, responding to painful stimuli only with eye opening, moaning and withdrawal of the extremities. Both plantar responses were extensor. Another brain CT did not show any changes compared to the previous scan. Lumbar puncture yielded clear, colorless fluid with a protein level of 0.85 g/l (normal 0.15–0.4), normal glucose, seven red blood cells and two white blood cells per high power field. A few hours later, the patient had serial GTC seizures and received an intravenous loading dose of phenobarbital. Despite a serum phenytoin level of 100 μmol/l and phenobarbital level of 150 μmol/l, she developed SE. Over 8 h she had approximately 40 seizures, each beginning with clonic activity of the left arm that secondarily generalized. EEG revealed BIPLEDs and in a 25 min recording, five clinical and two electrographic (subclinical) seizures occurred (Fig. 1). Laboratory studies revealed a platelet count of 190,000 mm−3, creatinine 270 μmol/l, and fibrinogen of 2.6 g/l. Blood, sputum and urine cultures were negative.
Figure 1EEG during SE showing markedly disorganized background, BIPLEDs and onset of a focal seizure in the right hemisphere.
Treatment with intravenous pentobarbital infusion was initiated to induce a burst suppression pattern on EEG, after which her seizures ceased. Plasmapheresis was resumed daily for 3 days followed by three more sessions every other day. The pentobarbital infusion was gradually tapered and discontinued after 5 days and the EEG was monitored to ensure no return of electrographic seizures. The next day she opened her eyes to loud voices but did not follow commands. EEG revealed diffuse slowing without epileptiform activity. Over the next several days her mental status gradually improved, blood counts and clotting studies returned to normal, and she was discharged from the hospital without neurological deficits. A subsequent EEG was normal. At last follow-up, 3 years after the illness, she remained seizure free with a normal neurological examination.
Discussion
Our patient demonstrated the diagnostic pentad for TTP, including the presence of thrombocytopenia, microangiopathic hemolytic anemia, neurological abnormalities, renal impairment and fever. This syndrome usually occurs in younger individuals. The median onset is 35 years; only 6% of the patients are older than 60 years.
In a review of 529 patients with TTP, the most common neurological manifestations were alteration of mental status (35%), headache (32%), coma (24%), focal weakness (24%), aphasia (19%), seizures (15%), and visual changes (10%).
These and other clinical features are believed to be due to widespread vascular occlusions caused by characteristic hyaline thrombi in terminal arterioles and capillaries.
Neuropathological changes include small vessel occlusion in the cortical and subcortical grey matter, some of which are associated with small infarctions.
Although our patient was in convulsive SE, two of her seizures were subclinical. This stresses the importance of a high level of suspicion for the possibility of SE in patients with TTP, especially in those with alteration in level of awareness or those in coma.
To our knowledge, no case with EEG findings of PLEDs or BIPLEDs associated with TTP has been reported in the literature. PLEDs are usually associated with seizures and carry an increased risk of mortality.
The BIPLEDs seen in our patient’s EEG suggested an acute and multifocal ischemic insult. The subsequent disappearance of those discharges and the return of normal background activity, coinciding with clinical improvement, indicate that the ischemic insult in this patient was largely reversible and that PLEDs in this syndrome are not necessarily indicative of a permanent structural lesion.
Despite her advanced age, our patient responded to treatment with plasmapheresis and pentobarbital induced coma. In the past, recurrent seizures and progression into coma constituted a frequent terminal event.
Improved survival has been attributed to treatment with plasma infusions and plasmapheresis. Current recommendations for treatment also include antiplatelet agents, corticosteroids, and in resistant cases, splenectomy and vincristine.
This case illustrates that complete neurological recovery is possible even when fulminant TTP is complicated by convulsive SE. It also suggests that the presence of PLEDs in this syndrome is not necessarily indicative of a permanent structural lesion. The transient nature of this EEG finding is fully consistent with a reversible ischemic insult.
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