MRI reveals multiple reversible cerebral lesions in an attack O f acute intermittent porphyria Article abstract-A 20-year-old woman had an attack of acute intermittent porphyria (AIP) with seizures and hallucinations. MRI revealed multiple lesions in both hemispheres. Both the cerebral clinical abnormalities and the MRI lesions resolved following treatment. These findings suggest that a vascular mechanism may underlie the pathogenesis of cerebral dysfunction in AIP. NEUROLOGY 1991;41:1300-1302 Peter H. King, M D , a n d Andrew C. Bragdon, MD Acute intermittent porphyria (AIP) is an uncom- era1 physical examination was unremarkable. The neurologic examination at this time was notable for normal mental stamon heritable disease in which deficiency of t h e enzyme tus, diffuse muscle atrophy, flaccid quadriplegia with trace porphobilinogen (PBG) deaminase leads to overmovement of the proximal limbs, and absent deep tendon production of t h e heme precursors 6-aminolevulinic reflexes. Plantar responses were flexor bilaterally. Pinprick acid (ALA) and PBG by t h e liver.' Neurologic dysfuncand joint position sensibilities were mildly diminished distally tion is a primary feature of this disease, with seizures in the extremities. EMG and nerve conduction studies were and encephalopathy being t h e hallmarks of cerebral consistent with a diffuse sensorimotor axonal neuropathy, involvement. preferentially involving motor neurons. Lead, mercury, and T h e pathogenesis of t h e cerebral manifestations rearsenic in a 24-hour urine sample were all normal. mains unclear. Some have suggested that metabolic The diagnosis of AIP was confirmed by the followingstudies (normal values in parentheses). RBC PBG deaminase was abnormalities produce diffuse neuronal dysfunction 17.5 nmol uroporphyrin/ml RBC/hr at 37 "C (20.9 to 42.2). A t h r o u g h e i t h e r a n o v e r a b u n d a n c e of c e r t a i n bio24-hour urine sample contained ALA 39 mg (<4), PBG 83 mg chemical factors (eg, PBG, ALA, or tryptophan) or a (<4), uroporphyrin 1,298 pg (<50), and coproporphyrin 132 deficiency of other factors (eg, heme or pyridoxal phospg (50 to 280). A stool sample contained (per 100 grams wet phate) stemming from t h e primary metabolic defect.' weight) protoporphyrin 2,160 pg (<3,416), uroporphyrin 871 Others have suggested that multifocal ischemia from a pg (<138), and coproporphyrin 1,620 pg (<1,002). After vascular process, possibly vasospasm, is r e ~ p o n s i b l e . ~ - ~treatment with a high carbohydrate diet and two courses of T h e disparate nature of these hypotheses derives, in hematin therapy, her biochemical indices of disease activity part, from the wide range of neuropathologic findings in normalized, but she remained quadriplegic. autopsy studies. Findings of n o abnormality2 or mild, Three months after admission, a gastrostomy tube was placed because of persistent difficulty maintaining adequate patchy neuronal loss and demyelination3 have favored oral intake. Drugs administered for the procedure were nitrous metabolic hypotheses, whereas findings of focal ischeoxide, 200 pg of fentanyl given intravenously, and 29 ml of 1% mic or necrotic cerebral lesion^^.^ have directed thinklidocaine injected locally. Abdominal pain and nausea foling toward a vascular m e c h a n i s m . However, t h e lowed for the next few days. On the 5th postoperative day, she pathologic findings may have been biased by problems had a left adversive seizure with secondary generalization. She inherent in autopsy studies. Cases in which cerebral was lethargic and confused for several hours afterward but was manifestations have been episodic and not clearly proxotherwise unchanged neurologically. Her blood pressure, imate to t h e patients' deaths are potentially biased which normally ranged between 110/70 and 120/90, rose trantoward normal or minimal findings. I n other cases, siently to 170/120. The general physical examination, includcomplications of chronic illness, such as poor nutrition, ing the funduscopic examination, was otherwise normal. Serum chemistries were remarkable for a sodium of 128 mmol/ and terminal complications, such as sepsis a n d pro1, a magnesium of 1.2 mg/dl (normal, 1.6 to 2.2 mg/dl), and an longed hypoxia from ventilatory depression, appear t o arterial PO, of 64 mm Hg. have contributed t o t h e severe neuropathologic lesions. Despite correction of these abnormalities, on the 6th postMRI provides a sensitive tool to examine changes operative day she had two more seizures similar to the first. occurring in t h e brain at t h e time of t h e acute attack Later that day she experienced visual hallucinations. An EEG without these confounding variables. We now report showed diffuse slowing at about 1 Hz but no epileptiform finding transient, multifocal, cerebral lesions with MRI activity. A brain CT without contrast enhancement was norat t h e time of an acute attack of AIP with cerebral mal except for a single questionable punctate low density in manifestations. The similarity in appearance of these the left basal ganglia. CSF was normal. An echocardiogram, lesions t o those found i n known vasculopathies, a n d including a microcavitation study to exclude right-to-left shunting, was normal. their resolution over time, provide support for t h e vasBrain MRI, performed on the 8th postoperative day, recular hypotheses of the pathogenesis of cerebral dysvealed seven cortically based, gyriform lesions located prifunction in AIP. marily in the frontal and parietal areas of both hemispheres Case report. A 20-year-old woman was transferred to Duke (figure, A). The PBG content in a 24-hour urine sample was University Medical Center with a 14-weekhistory of fluctuatmarkedly elevated at 143 mg. After a third course of hematin, ing weakness, abdominal pain, and hallucinations. A t the time her urinary PBG excretion fell to 24.7 mg/24 hr, and her abdominal pain and hallucinations resolved completely. No of transfer, vital signs were blood pressure, 130/100; heart rate, additional seizures occurred, and she was not placed on anti100; respiratory rate, 22; and temperature, 37.2 "C. The gen1300 NEUROLOGY 41 August 1991 Figure. Axial T,-weighted MRI images obtained (A) during the attack, showing multiple areas of increased signal intensity, and (B) 10 days later, showing resolution of these abnormalities. epilepticmedication.MRI repeated on the 18thpostoperative day showed that the lesions had resolved completely (figure, B). Discussion. In this patient, transient cerebral MRI abnormalities occurred coincident with an attack of AIP with typical cerebral manifestations. Although it is not specific for etiology, this pattern of multiple, discrete cortical lesions that resolve with time occurs with vasculopathies, including systemic lupus erythematoS U S , ~CNS vas~ulitis,~ and hypertensive encephalopathy,8 suggesting that a vascular process producing multifocal ischemia may have been responsible for the clinical presentation in our case. The notion that a vascular mechanism with resultant ischemia might underlie the cerebral dysfunction in AIP has been offered by several investigators since the 1940s.This hypothesis has been based in part on the autopsy findings mentioned above but receives further support from some physiologic observations. First, vasospasm occurs peripherally in both skin and retinal vessels during acute attacks of AIP.3,4Second, a rise in blood pressure frequently occurs concurrent with the onset of cerebral manifestation^.^*^ Moreover, the cerebral manifestations of AIP are quite similar to those of malignant hypertension, a condition in which the pathogenetic mechanism is presumed to be vascular. The mechanisms underlying the hypertension and vasospasm in AIP are unknown. However, parenterally administered porphyrins may cause hyperten- ion.^ An alternative explanation is that the lesions were induced by the patient's seizures. However, reports of reversible imaging abnormalities during or after seizures are rare, and in all such reports we have located, the patients have had focal status epilepticus.l0 There was no evidence of this in our patient. The present finding of multiple, reversible cerebral lesions provides new fuel for the notion that a vascular mechanism may underlie the cerebral manifestations of AIP, and should rekindle interest in this problem. From the Division of Neurology (Dr. King), Duke University Medical Center, Durham, NC, and the VA Medical Center and the Departments of Neurology and Pharmacology (Dr. Bragdon), SUNY Health Science Center, Syracuse, NY. Received November 1,1990. Accepted for publication in final form February 2, 1991. Address correspondence and reprint requests to Dr. Peter H. King, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. References 1. Kappas A, Sassa S, Galbraith RA, Nordmann Y. The porphyrias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill, 1989:1320-1329. 2. Berg M. Acute porphyria: clinical and pathological observations. Arch Intern Med 1945;76:335-340. 3. Denny-Brown D, Sciara D. Changes in the nervous system in acute porphyria. Brain 1945;68:1-16. 4. Hierons R. Changes in the nervous system in acute porphyria. Brain 1957;80:176-192. 5. Lai C-W, Hung T-P, Lin WSJ. Blindness of cerebral origin in acute intermittent porphyria: report of a case and postmortem examination. Arch Neurol 1977;34:310-312. 6. Aisen AM, Gabrielsen TO, McCune WJ. MR imaging of systemic lupus erythematosus involving the brain. AJR Am J Roentgenol August 1991 NEUROLOGY 41 1301 1985;144:1027-1031. 7. Miller DH, Ormerod IE, Gibson A, et al. MR brain scanning in patients with vasculitis: differentiation from multiple sclerosis. Neuroradiology 1987;29:226-231. 8. Hauser RA, Lacey DM, Knight MR. Hypertensive encephalopathy: magnetic resonance imaging demonstration of reversible cor- with serum-soluble interleukin-2 receptor levels in GuillainBar& syndrome tical and white matter lesions. Arch Neurol 1988;45:1078-1083. 9. Rask EN, Howell WH. The photodynamic action of hematoporphyrin. Am J Physiol 1928;84:363-377. 10. Kramer RE, Liiders H, Lesser RP, et al. Transient focal abnormalities of neuroimaging studies during focal status epilepticus. Epilepsia 1987;28:528-532. Article abstract-In patients with Guillain-Barre syndrome (GBS) soluble interleukin-2 receptor (sIL-2R) levels were elevated compared with those of patients with other neurologic diseases (OND), and of healthy controls. Smaller increases in sIL-2R levels occurred in OND patients compared to healthy subjects. Monitoring of GBS patients clearly demonstrated that decreases in sIL-2R levels correlated with clinical recovery. Thus, T-cell activation may be relevant in the pathogenesis of GBS. NEUROLOGY 1991;41:1302-1305 S. Bansil, M D ; F.A. M i t h e n , M D , PhD; S.D. Cook, M D ; A. Sheffet, P h D ; and C. Rohowsky-Kochan, PhD Guillain-Barre syndrome (GBS)is a demyelinating polyneuropathy presumably of autoimmune pathogenesis. Increased numbers of DNA-synthesizing lymphoblasts correlating with disease activity a r e present in the blood of GBS patients.' T h e interleukin-2 receptor (IL-2R) expressed o n activated T lymphocytes is shed, resulting in increases i n serum-soluble IL-2R (sIL-2R). Increases in circulating IL-2R T-lymphocytes2and i n serum sIL-2R concent r a t i o n ~were ~ found i n GBS patients. W e assessed serum concentrations of sIL-2R i n patients w i t h G B S , other polyneuropathies, and CNS diseases a n d i n healthy controls. Serial serum sIL-2R levels i n GBS patients were correlated with clinical disease activity. + Methods. Subjects. The table summarizes the characteristics of patients and controls. GBS. - These patients fulfilled the diagnostic criteria for G B S 4 Initial sera were drawn within a mean of 11.4 (f 5 [SD]) days after motor onset of disease. Serial samples were obtained from six GBS patients for 3 to 15 months. Disease severity was scored on a clinical scale of 0 to 5 , with 0 = healthy and 5 = requiring assisted ~ e n t i l a t i o n .Initially, ~ three patients were clinical grade 2,two grade 3, six grade 4, and three grade 5 . Other neurologc disease controls were patients with other polyneuropathies (OND-PNS): monoclonal gammopathy ( l ) , diabetes and sarcoidosis (l),diabetes and hypothyroidism ( I ) , diabetes and multiple myeloma (l),Charcot-Marie-Tooth disease ( I ) , ischemic polyneuropathy ( l ) ,neurofibromatosis (I), and unexplained polyneuropathy (1). Patients with CNS disorders (OND-CNS) included those with epilepsy ( 7 ) ,acute strokes ( 5 ) ,dementia (2), Parkinson's disease (2), spondylitic myelopathy ( I ) , and glomus jugular tumor (1). Family controls were healthy relatives-spouses (2), siblings ( 2 ) , identical twin (I),and parent (1)-in contact with a GBS patient. One individual had a viral illness similar to that of the paired GBS patient. Serum was drawn within 3 weeks of motor disease onset in the paired GBS patient. Healthy controh were individuals with no recent contact 1302 NEUROLOGY 4 1 August 1991 with a GBS patient and no medical disease. S e r u m collection. Serum was collected, handled identically, and stored at -70 "C until testing. GBS and family control samples were collected over 1 to 5 years, and OND and healthy control sera were obtained over 1 to 3 years. Repeated freezing and thawing of sera was avoided. sZL-2R assay. Serum sIL-2R levels were measured by ELISA using a kit (T Cell Sciences, Cambridge, MA) as de~ c r i b e d All . ~ sera were assayed two or more times with less than 10% variability between testing. All sera were tested undiluted; however, two GBS sera were retested a t a 1: 10 dilution. Statistical analysis. Mean sIL-2R levels among GBS, OND-PNS, OND-CNS, and healthy controls were compared by the Kruskal-Wallis test, and mean sIL-2R levels between each group by Fisher's least significant difference. The rank sum test was performed on the six GBS patients and family Table. Characteristics of patient a n d control populations Guillain-Barre 14 7 17 syndrome Other neurologic 8 216 Other neurologic CNS diseases Family controls 18 4/14 6 3/3 Healthy controls 34 13/21 PNS diseases 42 (19-77) 49 (29-74) 47 (25-76) 38 (19-69) 37 (23-79) * No individual in the patient or cuntrol groups had received cortico- 1 steroids. other immunosuppressive therapy, or plasmapheresis at the time of initial blood drawing. No subject in any of the groups was HIVpositive or had risk factors for developing HIV infection.