OBSERVATION

Corticosteroid-Responsive Postmalaria
Encephalopathy Characterized by Motor Aphasia,
Myoclonus, and Postural Tremor
Hans Schnorf, MD; Karin Diserens, MD; Hans Schnyder, MD; Michel Chofflon, MD;
Louis Loutan, MD; Virginia Chaves, MD; Theodor Landis, MD

Objectives: To study the clinical spectrum of an acute
severe encephalopathy occurring in 2 patients after recovery from falciparum malaria infection and to compare it with the reported clinical features of the postmalaria neurological syndrome.
Design: Case report.
Setting: Tertiary care hospital.
Patients: Two patients presented with acute onset of

fluctuating motor aphasia, severe generalized myoclonus, and postural tremor. Additional signs were cerebellar ataxia, and in 1 patient, generalized epileptic seizures. Magnetic resonance imaging of the brain revealed
patchy white matter lesions in 1 patient. Clinically, the
patients’ conditions continued to worsen until cortico-

steroids were introduced, the use of which induced a rapid,
albeit incomplete, recovery.
Conclusions: We describe a new, severe variant of
the still poorly defined postmalaria neurological syndrome. We propose a preliminary classification of this
syndrome, according to its clinical characteristics, as
follows: a mild or localized form, characterized by isolated cerebellar ataxia or postural tremor; a diffuse,
but relatively mild encephalopathic form, characterized by acute confusion or epileptic seizures; and a
severe, corticosteroid-responsive encephalopathy that
is characterized by motor aphasia, generalized myoclonus, postural tremor, and cerebellar ataxia.

Arch Neurol. 1998;55:417-420

A

From the Department of
Neurology (Drs Schnorf,
Diserens, Chofflon, Chaves, and
Landis) and the Travel and
Migration Medicine Unit,
Department of Community
Medicine (Dr Loutan),
University Hospital of Geneva,
Geneva, Switzerland; and the
Department of Neurology,
University of Zürich, Zurich,
Switzerland (Dr Schnyder).

SMALL number of published observations on
neurological disease following successfully treated
Plasmodium falciparum
malaria has increased awareness of the
postmalaria neurological syndrome
(PMNS).1-3 However, both the clinical
spectrum and the etiology of this syndrome are still poorly defined. Isolated cerebellar ataxia following P falciparum malaria has been described in patients from
Sri Lanka.1 More recently, a group from
Vietnam observed an acute confusional
state or generalized convulsions in a number of patients recovering from P falciparum malaria.2 These patients had complete recovery without specific therapy.
We report a new and severe variant
of PMNS. Two patients who had recovered from a recent severe P falciparum malarial infection developed an acute encephalopathy with fluctuating motor
aphasia, severe generalized myoclonus, and
postural tremor. Clinical deterioration continued until the introduction of corticosteroids, the use of which induced a rapid,

but incomplete, recovery. Possible pathomechanisms of this encephalopathy are
discussed.
REPORT OF CASES

PATIENT 1
A 34-year-old woman was diagnosed as
having mixed infection with P falciparum
(45% parasitemia) and Plasmodium vivax
12 days after returning from a trip to Africa, where she took a homeopathic preparation as malaria prophylaxis. She was febrile (body temperature, 39.2°C),
somnolent, disoriented, mildly icteric, and
had otherwise normal results of the neurological examination. Her hemoglobin
level was 8.7 g/L and platelets were
306 0003109/L. She was treated with intravenous quinine sulfate (10 mg/kg 3
times per day for 3 days), clindamycin hydrochloride (10 mg/kg twice daily for 7
days), blood exchange transfusion (3.5 L),
and fibrinogen. She developed complications of severe hemolysis, disseminated intravascular coagulation, and acute renal

ARCH NEUROL / VOL 55, MAR 1998
417

©1998 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a UNIVERSITY OF EXETER User on 07/18/2016

T2-weighted axial magnetic resonance imaging sections from patient 1 showing hyperintense focal lesions in the left cella media (left) and the deep cerebellar
white matter, most prominent dorsolateral to the right dentate nucleus (right).

failure necessitating hemofiltration and hemodialysis. Four
days after admission there was no parasitemia and her
mental status had gradually normalized. Twenty-one days
after admission she became febrile again (body temperature, 38.2°C), irritable, restless, had important word finding difficulties, difficulties in naming objects, postural
tremor of the arms, and mild cerebellar ataxia of gait and
extremities. Examination of the cerebrospinal fluid (CSF)
showed a white blood cell count of 0.013109/L (95% lymphocytes and 5% monocytes) and a protein level of 0.6
g/L without oligoclonal distribution. Results of extensive serologic studies and cultures, both in serum and
CSF, were negative. Peripheral blood smears remained
negative for malaria parasites. Results of cranial computed tomography (CT) were normal and cranial magnetic resonance imaging (MRI) showed hyperintense lesions in periventricular and supraventricular areas and
in the cerebellum, some of which showed gadolinium enhancement (Figure). An electroencephalogram revealed mild to moderate slowing of background activity
and intermittent dysrhythmic discharges. During the following days she developed generalized stimulussensitive myoclonus, continued to have expressive aphasia that fluctuated in severity, and had 2 tonic-clonic
epileptic seizures. Treatment with phenytoin was started.
Ceftriaxone sodium (2 g every 12 hours) and acyclovir
(10 mg/kg every 8 hours) were empirically given for 6
days, with no clinical improvement. Treatment with intravenous methylprednisolone sodium succinate was
started 9 days after the appearance of fever and neurological symptoms (100 mg/d for 3 days with subsequent

tapering for 10 days). Twenty-four hours after the initiation of corticosteroid therapy the patient was afebrile, and had significant improvement of aphasia and
myoclonus. When discharged 2 weeks later all of the patient’s neurological abnormalities had resolved, except
for postural tremor of the arms.
PATIENT 2
A 61-year-old man, who had spent several years working in Central Africa, was diagnosed as having P falciparum malaria (50% parasitemia) 5 days after returning from
a business trip to Cameroon. He had taken no antimalaria prophylaxis. He consumed sustained moderate
amounts of alcohol and was known for years to have intermittent mild tremor of the hands. He was febrile (body
temperature, 39.2°C), somnolent, disoriented to space,
dehydrated, mildly icteric, and had petechial lesions on
both lower legs. His hemoglobin level was 13.5 g/L; platelet count, 70003109/L, and leukocyte count, 3.23109/L.
Cytomegalovirus (CMV) serologic test results were positive (IgG, 2.7 g/L [normal, ,15]; IgM, 0.74 g/L [normal, ,0.6 g/L]). He was treated with intravenous quinine sulfate (10 mg/kg 3 times daily for 3 days) and
doxycycline (200 mg/d), followed by mefloquine hydrochloride (1500 mg). A blood exchange transfusion (3 L)
was given on day 1. Four days after admission blood
smears were negative for parasites, he made an uneventful recovery, and he was discharged 1 week after admission. Ten days later he was readmitted because of irritability, word finding difficulties, and headache. He was

ARCH NEUROL / VOL 55, MAR 1998
418

©1998 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a UNIVERSITY OF EXETER User on 07/18/2016

afebrile, restless, oriented, and had word finding and naming difficulties. He had postural tremor of the arms and
rare myoclonic twitches of his face and extremities. Examination of the CSF showed a white blood cell count
of 0.063109/L (97% lymphocytes and 3% monocytes) and
a protein level of 1.87 g/L (g-globulin, 0.28 g/L without
oligoclonal distribution). Blood serologic test results were
positive for CMV (IgG, 7.4 g/L; IgM, 2.27 g/L), EpsteinBarr virus (EBV) (IgG .1:160; IgM positive) and varicellazoster virus (VZV) (IgG, 0.6 g/L [normal, ,0.2 g/L]; IgM
negative). Test results for EBV were negative twice. His
CSF was negative for antibodies against CMV, EBV, and
mildly positive for VZV (IgG, 0.57 g/L; IgM negative).
Repeated polymerase chain reaction testing , performed
in 3 subsequent CSF specimens, revealed negative results for CMV, EBV, VZV, and herpes simplex virus. Cultures of blood, CSF, and urine were sterile. An electroencephalogram revealed mild slowing of background
rhythm and theta-delta activity over the left temporocentral region. Findings of cranial CT and MRI scans were
normal except for mild cerebral atrophy. On the day after readmission, body temperatures up to 38°C recurred. Repeated blood smears were negative for malaria parasites. Empirical treatment with halofantrine
hydrochloride (500 mg 3 times daily) was given, with
no benefit. The patient developed ataxia of gait, severe
generalized myoclonus, which was sensitive to auditory
and tactile stimuli, and continued to have expressive aphasia of fluctuating severity. A CSF culture was sterile, with
a white blood cell count of 0.083109/L (87% lymphocytes and 12% monocytes) and a protein level of 1.8 g/L,
without oligoclonal distribution. Because of a positive serologic test result for schistosomiasis, praziquantel was
given (60 mg/kg). Twelve days after the appearance of
neurological symptoms, prednisone therapy was started
at a dose of 60 mg orally and continued for 4 days. Twentyfour hours after initiating prednisone therapy the fever
disappeared and the neurological abnormalities improved rapidly, which continued after the drug regimen
was stopped. Another CSF culture 25 days after readmission was sterile, with a white blood cell count of
0.013109/L (93% lymphocytes and 6% monocytes), and
a protein level of 0.6 g/L (g-globulin, 0.37 g/L with 3 oligoclonal bands). Levels of anti−VZV IgG were mildly elevated in CSF (0.35 g/L), while complement-fixation and
anti-VZV IgM test results were negative. On the 26th day
the patient was discharged after normal neurological examination results were obtained, with a residual postural tremor of the arms.
COMMENT

The neurological symptoms observed in these patients
enlarge the clinical spectrum of PMNS. This syndrome
has been defined as the acute onset of confusion or epileptic seizures, occurring in a patient without parasitemia, with a latency of several days to weeks, after
recovery from successfully treated P falciparum
malaria.2 Furthermore, postmalaria isolated cerebellar
ataxia, which has been mainly observed in Sri Lanka,
should be considered a mild variant of PMNS.1 Our
patients’ encephalopathy was characterized by fluctuat-

ing motor aphasia, severe generalized myoclonus, postural tremor, and cerebellar ataxia. One patient had
generalized epileptic seizures. While previously
described patients recovered spontaneously and completely, our patients’ conditions deteriorated, showed
clinical improvement only on the introduction of corticosteroid therapy, and had residual postural tremor.
Three patients with isolated cerebellar ataxia described
in Sri Lanka were transiently given corticosteroids with
possible beneficial effects on the speed of recovery of
their ataxia.1 The neurological involvement of PMNS
thus ranges from limited and mild, as exemplified by
isolated cerebellar ataxia1 or isolated postural tremor,2
to that of a diffuse encephalopathy, which is either mild
and self-limiting2 or severe and necessitating corticosteroid treatment. We propose that PMNS be classified
according to its clinical characteristics into (1) a mild or
localized form characterized by isolated cerebellar
ataxia or postural tremor; (2) a diffuse, but relatively
mild encephalopathic form, characterized by acute confusion or epileptic seizures; and (3) a severe,
corticosteroid-responsive encephalopathy that is characterized by motor aphasia, generalized myoclonus,
postural tremor, and cerebellar ataxia. However, to
some extent, clinical features may overlap between the
3 forms, as exemplified by our patients, in whom we
observed cerebellar ataxia in addition to the clinical
syndrome described earlier.
The etiology of PMNS remains unclear, but immune mechanisms may play a dominant role and have
been implicated in postmalaria cerebellar syndrome.4 Neurological symptoms in most patients with PMNS, including ours, develop with a latency after acute malarial infection, similar to acute disseminated encephalomyelitis
following a viral or mycoplasmal infection.5-7 Magnetic
resonance imaging studies in patient 1 revealed several
discrete white matter lesions (Figure) that have not been
reported previously in PMNS, and which are reminiscent of the radiological abnormalities seen in mild cases
of acute disseminated encephalomyelitis.5,6 The favorable clinical response to corticosteroid therapy witnessed in our patients supports the hypothesis of an underlying immune mechanism. It is unlikely that the initial
bout of malaria resulted in the white matter lesions in
patient 1, because during the period of acute malaria,
her neurological status was normal except for initial mild
somnolence.
Coinfection with a virus capable of causing encephalitis has been suggested as another possible mechanism
implicated in the pathogenesis of some cases of PMNS.2
Patient 2 had elevated levels of IgG and IgM antibodies
against CMV and EBV in serum, but not in CSF. He also
had raised titers of anti-VZV IgG antibodies in serum and
CSF and oligoclonal distribution of immunoglobulins in
his third CSF examination. Although polymerase chain
reaction repeatedly failed to detect genomic material for
VZV, EBV, and CMV in the CSF, the possibility cannot
be excluded that a reactivated herpesvirus, especially VZV,
participated in the pathogenesis of the encephalopathy
in this patient.
This report does not clarify the role of mefloquine
in the pathogenesis of PMNS, which had been given to

ARCH NEUROL / VOL 55, MAR 1998
419

©1998 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a UNIVERSITY OF EXETER User on 07/18/2016

only 1 of our patients. Mefloquine has been identified as
a risk factor for PMNS1 and may have adverse effects, such
as acute confusion and generalized convulsions.8,9 Neither mefloquine nor halofantrine, which was given to patient 2, has been associated with the neurological symptoms seen in our patients.8-10
We conclude that the clinical spectrum of PMNS is
broader than previously recognized and includes a distinct syndrome of motor aphasia, generalized myoclonus, and postural tremor. This severe variant of PMNS
should prompt early corticosteroid treatment, which induced rapid clinical recovery in our patients. Our proposed preliminary classification of this syndrome should
alert the clinician that corticosteroid therapy, while not
necessary in most cases of PMNS, is indicated in a severe, progressive variant, with patients being severely disabled by their symptoms and not showing any signs of
spontaneous recovery.
Accepted for publication September 9, 1997.
Corresponding author: Hans Schnorf, MD, Central Hospital, Avarua, Rarotonga Island, Cook Islands.

REFERENCES
1. Senanayake N, De Silva HJ. Delayed cerebellar ataxia complicating falciparum
malaria: a clinical study of 74 patients. J Neurol. 1994;241:456-459.
2. Mai NTH, Day NPJ, Chuong LV, et al. Post-malaria neurological syndrome. Lancet. 1996;348:917-921.
3. Chaine P, Woimant F, Corabianu O, et al. Isolated cerebellar syndrome: an atypical form of cerebral malaria. J Neurol Neurosurg Psychiatry. 1991;54:655.
4. De Silva HJ, Hoang P, Dalton H, et al. Immune activation during cerebellar dysfunction following falciparum malaria. Trans R Soc Trop Med Hyg. 1992;86:129131.
5. Caldemeyer KS, Smith RR, Harris TM, et al. MRI in acute disseminated encephalomyelitis. Neuroradiology. 1994;36:216-220.
6. Kesselring J, Miller DH, Robb SA, et al. Acute disseminated encephalomyelitis:
MRI findings and the distinction from multiple sclerosis. Brain. 1990;113:291302.
7. Pellegrini M, O’Brien TJ, Hoy J, et al. Mycoplasma pneumoniae infection associated with an acute brainstem syndrome. Acta Neurol Scand. 1996;93:203206.
8. Rouveix B, Bricaire F, Michon C, et al. Mefloquine and an acute brain syndrome.
Ann Intern Med. 1989;110:577-578.
9. Weinke T, Trautmann M, Held T, et al. Neuropsychiatric side effects after the use
of mefloquine. Am J Trop Med Hyg. 1991;45:86-91.
10. Villota Arrieta J, Barrieira Casal B, Garcia Lopez M, et al. The halofantrine treatment of Plasmodium falciparum malaria: clinical experience. An Esp Pediatr. 1996;
44:117-120.

Announcement
Free Patient Record Forms Available
Patient record forms are available free of charge to
ARCHIVES readers by calling or writing FORMEDIC, 12D
Worlds Fair Dr, Somerset, NJ 08873-9863, telephone
(908) 469-7031.

ARCH NEUROL / VOL 55, MAR 1998
420

©1998 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a UNIVERSITY OF EXETER User on 07/18/2016