Epilepsy in children with infantile thiamine deficiency

Published Ahead of Print on July 1, 2009 as 10.1212/WNL.0b013e3181b121f5

                                    Epilepsy in children with infantile
                                    thiamine deficiency

A. Fattal-Valevski, MD              ABSTRACT
A. Bloch-Mimouni, MD                Objective: To report the follow-up findings of 7 children with severe epilepsy as a result of thia-
S. Kivity, MD                       mine deficiency in infancy caused by a defective soy-based formula.
E. Heyman, MD
                                    Methods: The medical records of 7 children aged 5– 6 years with thiamine deficiency in infancy
A. Brezner, MD
                                    who developed epilepsy were reviewed and their clinical data, EEG tracings, and neuroimaging
R. Strausberg, MD
                                    results were recorded. The clinical course and present outcome of these children, now 5 years
D. Inbar, MD
                                    after exposure to thiamine deficiency, are described.
U. Kramer, MD
H. Goldberg-Stern, MD               Results: All infants displayed seizures upon presentation, either tonic, myoclonic, or focal. Six
                                    infants had an EEG recording at this stage and all showed slow background. Five of them had no
                                    epileptic activity and only 1 displayed focal activity. Following a seizure-free period of 1–9
Address correspondence and          months, the seizures recurred, and all 7 children displayed either myoclonic or complex partial
reprint requests to Dr. Aviva       seizures. Multifocal or generalized spike wave complexes were recorded on the EEGs of all 7
Fattal-Valevski, Pediatric
Neurology Unit, Dana Children’s     patients, and the tracings of 3 children evolved into hypsarrhythmia. The seizures were refractory
Hospital, Sourasky Medical          to most antiepileptic drugs, and 4 children remain with uncontrolled seizures. All children have
Center, 6 Weitzman St., Tel Aviv,
64239, Israel
                                    mental retardation and motor disabilities as well as symptoms of brainstem dysfunction.
afatal@post.tau.ac.il               Conclusions: Our findings indicate that severe infantile thiamine deficiency may result in epilepsy.
                                    Neurology® ●●●

                                    ACTH ⫽ adrenocorticotropic hormone.

                                    In 2003, approximately 20 Israeli infants were seriously affected after being fed an international
                                    brand of soy-based formula, later found to be deficient in thiamine (vitamin B1).1,2 The for-
                                    mula was withdrawn from the shelves and the public warned against its continued use.3,4 The
                                    manufacturer reported that the formula had been altered in early 2003, and confirmed the absence
                                    of thiamine. The outcome of the infants was grave: 2 died of cardiomyopathy,3 and approximately
                                    10 remain with residual damage: 1 with complete atrioventricular block and permanent pacemaker,
                                    and others with ataxia, sensorineural hearing loss, swallowing difficulties, and a wide spectrum of
                                    psychomotor retardation. We report here only on those with severe epilepsy.
                                       The major manifestations of thiamine deficiency in humans involve the cardiovascular and
                                    nervous systems.5 Dry beriberi is characterized by sensorimotor neuropathy of the lower ex-
                                    tremities and wet beriberi by edema and congestive heart failure. Wernicke-Korsakoff syn-
                                    drome, most common in the Western world, mainly affects alcoholics and is characterized by
                                    confusion, ataxia, ophthalmoplegia, nystagmus, and impaired memory and cognition. It may
                                    also be seen in nonalcoholic patients with gastrointestinal diseases and other disorders associ-
                                    ated with malnutrition.6 Symptoms of thiamine deficiency may appear as early as 2 to 3 weeks
                                    on a deficient diet, since body storage of thiamine is minimal.5

Editorial, page XXX
                                    e-Pub ahead of print at www.neurology.org.
                                    From the Pediatric Neurology Unit (A.F.-V., U.K.), Tel Aviv Sourasky Medical Center; The Pediatric Neurology and Developmental Unit (A.B.-M.),
                                    Loewenstein Rehabilitation Hospital, Raanana; Epilepsy Service (S.K., H.G.-S.), Schneider Children’s Medical Center, Petach Tikva, Israel;
                                    Department of Child Neurology and Rehabilitation (E.H.), Assaf Harofeh Medical Center, Zerifin, Israel; Department of Rehabilitation (A.B.), Sheba
                                    Medical Center; Pediatric Neurology (R.S.), Schneider Children’s Medical Center, Petach Tikva, Israel; Child Development Center (D.I.), Schneider
                                    Children’s Medical Center, Petach Tikva, Israel, All affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel.
                                    Disclosure: The authors report no disclosures.

                                                                                                               Copyright © 2009 by AAN Enterprises, Inc.                            1
Infantile thiamine deficiency is very rare in                         encephalopathy and focal seizures. Her EEG showed diffuse
                                                                             background slowing and later left temporal spikes. MRI demon-
    developed countries, occurring mainly in breast-
                                                                             strated delayed myelinization and a thin corpus callosum. Brain-
    fed infants of mothers with inadequate thiamine                          stem auditory evoked response revealed decreased conduction
    intake.7,8 The onset of symptoms in infants is                           time in the pons. When thiamine deficiency was diagnosed, she
    often very rapid and the fatality rate is high.5                         was treated with phenobarbital and clonazepam and received IM
                                                                             thiamine, with improvement. In the following month, she began
    Seizures have been reported upon presentation                            to have multiple daily clusters of myoclonic seizures. EEG re-
    in children with infantile thiamine deficiency;                          flected multifocal epileptiform activity with secondary generali-
    however, residual epilepsy is extremely rare.9                           zation. At 6 months, it evolved into modified hypsarrhythmia
                                                                             that improved with vigabatrin. Currently, on a combination of
    METHODS The current study group consists of 7 children,                  vigabatrin and phenobarbital, she has only rare seizures, but her
    all girls aged 5– 6 years, who had infantile thiamine deficiency         EEG demonstrates multifocal epileptiform activity. She has spas-
    caused by a defective formula and consequently developed epi-            tic quadriplegia, severe mental retardation, microcephaly, and
                                                                             severe kyphoscoliosis. Due to repeated aspirations and pneumo-
    lepsy. All are being followed up in pediatric neurology clinics
                                                                             nia, she is ventilated via tracheostomy and fed via gastrostomy.
    and rehabilitation day care facilities in 4 medical centers in Israel.
    There is no ethnic predominance. Perinatal history was unre-             Case 3. This patient, a girl 5 years and 3 months of age, was
    markable; all were born at term: 1 by elective cesarean section          conceived via in vitro fertilization and fed with the soy-based
    and 2 by vacuum extraction. Only 1 of the children had a family          formula from 10 weeks of age. At 18 weeks, she presented with
    history of febrile convulsions (case 6). All medical records were        lethargy and nystagmus. Four days later, she was noted to have
    reviewed and clinical data on seizure semiology, frequency, and          left-sided focal seizures. EEG showed background slowing and
    treatment were compiled using a structured questionnaire. Data           electrographic seizure in the right frontal region associated with
    on EEG tracings and neuroimaging were recorded. The clinical             eye deviation. Phenobarbital was initiated with good control of
    course and the present outcome of the children, 5 years after            the seizures. CT and MRI demonstrated increased T2 signals in
    exposure to thiamine deficiency, are described. The study was            the thalamus, pons, and cortical regions. Lumbar puncture, in-
    approved by the Institutional Ethics Review Committee.                   cluding serology for viruses and PCR for herpes, and plasma
                                                                             aminoacids, ammonia, and urine organic acids, were all normal.
    Case 1. This patient, a girl 5 years and 3 months of age, initially
                                                                             She received pleconaril (an antiviral agent), IV immunoglobulin,
    breastfed, was switched to the soy-based formula at 3 weeks of
                                                                             and steroids. When thiamine deficiency was diagnosed, she was
    age. At 5 months, she presented with vomiting, fever, and oph-
                                                                             given thiamine IM. Phenobarbital was discontinued gradually
    thalmoplegia. She deteriorated rapidly, developing abdominal
                                                                             and she remains seizure-free. At 11 months of age, she presented
    distension and apneic episodes, followed by increased tone and
                                                                             again with focal seizures characterized by daily clusters of eye
    rigidity, myoclonic jerks, and coma requiring ventilation. Bacte-
                                                                             deviation to the left after awakening. EEG showed bilateral fron-
    riologic and virologic studies were negative. Lactic acid was ele-
                                                                             tal epileptiform activity of spike-wave complexes and polyspikes
    vated in blood (5.8 mmol/L) and CSF (6.6 mmol/L) (normal
                                                                             with secondary generalization. Subsequent EEGs deteriorated to
    range 1.1–2.3 mmol/L). Plasma aminoacids, ammonia, and                   secondary hypsarrhythmia.
    urine organic acids were normal. EEG upon admission showed                    At age 3, brain MRI demonstrated atrophy, delayed myelin-
    background slowing, with occasional bursts of right hemispheric          ization, and bilateral increased signals in the putamen. Her sei-
    sharp waves. MRI showed bilateral, symmetric, increased T2 sig-          zures failed to respond to phenobarbital, vigabatrin, or valproic
    nals in the basal ganglia, mammillary bodies, and periaqueductal         acid, but did respond to adrenocorticotropic hormone (ACTH)
    grey matter. A high lactate peak was detected in the brainstem on        injections. The EEG results improved gradually and 3 months
    magnetic resonance spectroscopy. Suspecting Leigh disease, em-           later she had only a mild slow tracing with no epileptiform activ-
    piric vitamin cocktail supplementation was initiated (including          ity. Currently, on vigabatrin, she is seizure-free. She has moder-
    enteral thiamine 500 mg/day). Clinical improvement was noted             ate mental retardation, strabismus, and left hemiparesis, but is
    the following day. Muscle biopsy revealed normal mitochondrial           able to walk with support.
    respiratory chain enzymes and microscopy. On day 7, thiamine
    deficiency was diagnosed by the thiamine pyrophosphate effect            Case 4. This patient, a girl 5 years and 3 months of age, born by
    (17.65%, normal values 0 –15%).                                          vacuum extraction, received milk formula for 6 weeks, and then
        After being discharged, she continued to have up to 25 daily         she was switched to the soy-based formula due to salmonella
    episodes of myoclonic jerks of the head and upper extremities.           infection. At 4 months, she became lethargic and displayed signs
    EEG showed spikes and slow wave discharges with activation               of encephalopathy. She deteriorated rapidly, with abnormal
    during sleep. After multiple drug failure—phenobarbital, phe-            breathing, seizures, and loss of consciousness, requiring ventila-
    nytoin, topiramate, valproic acid, and levetiracetam—she was             tion. She received phenobarbital and phenytoin. Brain MRI
    started on a ketogenic diet, with valproic acid. Three weeks later,      showed increased T2 signals in the brainstem and mammillary
    she was seizure-free and more alert. Repeat EEG showed almost            bodies. EEG showed slow background with no epileptiform ac-
                                                                             tivity. Brainstem auditory evoked response and visual evoked
    complete normalization. The diet was discontinued after 2 years,
                                                                             response testing showed abnormal conduction, which later im-
    at the age of 4. Currently, she is seizure-free with a normal EEG.
                                                                             proved. After being diagnosed with thiamine deficiency, the for-
    She walks with aid and has moderate mental retardation, micro-
                                                                             mula was discontinued and she was treated with thiamine. At 7
    cephaly, hypotonia, and ophthalmoplegia.
                                                                             months, while on phenobarbital maintenance therapy, she pre-
    Case 2. This 5-year-old girl was switched to the soy-based for-          sented with complex partial seizures and later with head drops.
    mula at 2 weeks due to intolerance to milk formula. At 6 weeks,          Modified hypsarrhythmia was seen on EEG. The seizures
    she was noted to have a weak cry, aphonia, and tonic seizures.           stopped with vigabatrin, and her EEG improved. Subsequent
    Only at 14 weeks was she brought to medical attention, with              EEGs showed multifocal epileptiform activity. Currently, she is

2   Neurology ●●●
seizure-free on phenobarbital and vigabatrin. She walks with a         without improvement. Presently, she is on a combination of fel-
walker and has moderate mental retardation, microcephaly, stra-        bamate, phenobarbital, and clobazam with considerable reduc-
bismus, hypotonia, and dystonia.                                       tion in seizure frequency to 1–2 seizures per week. She is unable
                                                                       to sit or stand independently and has severe mental retardation,
Case 5. This patient, a girl 5 years and 4 months of age, was
                                                                       microcephaly, vertical nystagmus, and hypotonia.
born by vacuum extraction. She developed normally until the
age of 8 months, when she was admitted for vomiting and verti-         Case 7. This 6-year-old girl was switched to the soy-based for-
cal nystagmus. Brain CT, EEG, abdominal ultrasound, and                mula due to diarrhea. She developed normally until 9 months,
urine for vanillylmandelic acid were normal. Five days later, she      when she became progressively weaker and lethargic with signs
developed lethargy and seizures. She deteriorated rapidly, failed      of hypotonia. Brain CT, thyroid function tests, plasma aminoac-
to respond to pain stimuli, and had severe apnea, requiring ven-       ids, and ammonia were normal; urine organic acid revealed gen-
tilation. A second EEG showed generalized moderate to severe           eral aminoaciduria. At 11 months, she had involuntary
slowing with no epileptic focus. MRI demonstrated diffuse sym-         movement of the left hand and displayed delayed development
metric abnormalities in the basal ganglia, brainstem, mammill-         and communication. At 14 months, the formula was substituted
ary bodies, and white matter. Brainstem auditory evoked                and she began receiving vitamin supplementation, with im-
response testing revealed severe abnormality in the lower brain-       provement. A brainstem auditory evoked response study showed
stem function on the left. Lactic acid was elevated in blood (38       impaired peripheral conduction. MRI at 16 months was normal.
mg/dL) and CSF (43.6 mg/dL) (normal 2–20 mg/dL) and she                At 20 months, she presented with myoclonic jerks of the left
was given multivitamin supplementation and coenzyme Q, with            hand and EEG showed paroxysmal spike and wave discharge.
mild improvement. The focal seizures persisted and she was             She was treated with valproic acid and later lamotrigine, with
treated with phenobarbital, phenytoin, and, later, topiramate.         improvement. A repeat EEG revealed paroxysmal spikes,
MRI showed brain atrophy and edema in the caudate and globus           polyspikes, and spike-wave discharge. Currently, on valproic
pallidum consistent with subacute necrotizing encephalopathy.          acid and lamotrigine treatment, she has only rare seizures. She is
Muscle biopsy revealed reduced activity of all respiratory chain       able to walk independently, but her walk is unstable. She is com-
complexes. Genetic study for mutations of Leigh disease (8993,         municative but her behavior is characterized by hyperactivity,
ATP-6) was negative. Thiamine deficiency was diagnosed 1
                                                                       impulsivity, short attention span, disinhibition, and abnormal
month later and she was treated IM with thiamine. Two months
                                                                       judgment. She has moderate mental retardation, hypotonia, and
later, she was discharged to a rehabilitation center on phenobar-
                                                                       stereotypic movements of her hands.
bital treatment with a tracheostomy and gastrostomy. At 1 year,
EEG displayed background slowing with multifocal epileptic ac-
                                                                       RESULTS The demographic and clinical character-
tivities which evolved into hypsarrhythmia and she was treated
with clonazepam, vigabatrin, and topiramate. She also had              istics of the study group are given in table 1. All pa-
dysautonomic symptoms of tachycardia and hypertension,                 tients displayed abnormal MRI findings except for
treated with propranolol. She was discharged after 18                  case 7, in whom the MRI was done 7 months after
months. Currently, she is in a persistent vegetative state, ven-       the acute symptoms. Upon presentation, all infants
tilated via tracheostomy, and has breathing difficulties due to
                                                                       had episodes of apnea, increased tone, or myoclonic
paralysis of her left diaphragm. She is on vigabatrin and topi-
ramate and has infrequent seizures during febrile illness. She
                                                                       jerks diagnosed as seizures. EEG recording at this
has spastic quadriplegia, ophthalmoplegia, kyphoscoliosis,             stage showed slow background in 6 infants; 5 dis-
and profound mental retardation.                                       played no epileptic activity and in 1 a focal electro-
                                                                       graphic seizure was recorded (table 2).
Case 6. This 5-year-old girl was switched to the soy-based for-
mula due to infantile colic at 4 weeks of age. At 8 weeks, she had         After the initial acute phase caused by the thia-
vomiting and diarrhea and became lethargic. Blood tests were           mine deficiency, there was a seizure-free period rang-
normal except for elevated blood lactate of 2.4 mmol/L (normal         ing from 1 to 9 months. Later, seizures recurred and
range 1.1–2.3 mmol/L). Two days later, she presented with sei-         were either myoclonic or complex partial; 3 infants
zures. Brain CT, EEG, and lumbar puncture were normal and
                                                                       had modified hypsarrhythmia on EEG. Antiepileptic
she was treated with phenobarbital. Later, there were apneic
spells and she was transferred to the pediatric intensive care unit.
                                                                       treatments included phenobarbital, phenytoin, topi-
MRI revealed delayed myelinization and brain atrophy. At 10            ramate, valproic acid, clonazepam, lamotrigine, leve-
weeks, she did not display eye-tracking or social smiling and did      tiracetam, vigabatrin, ACTH, prednisone, clobazam,
not respond to pain stimuli. Plasma aminoacids, ammonia, and           zonigram, and a ketogenic diet. Four children were
urine organic acids were normal, as were the brainstem auditory        refractory to all treatments and remain with uncon-
evoked response and visual evoked potential studies. EEG at 12
                                                                       trolled seizures. Three children are currently seizure-
weeks revealed sparse paroxysmal spikes and background slow-
ing. At 14 weeks, when the formula was discontinued and she
                                                                       free: 1 responded to treatment with ACTH, 1 to a
received thiamine injections, she became more alert and began to       combination of vigabatrin and phenobarbital, and 1
smile. The seizures gradually decreased and at 18 weeks she was        to a ketogenic diet. All but 1 still display EEG abnor-
discharged on clonazepam and valproic acid. Seizures recurred at       malities and receive antiepileptic drugs (table 2).
1 year and were tonic and sometimes myoclonic. EEG revealed                The present outcome of these children is grave.
right occipital epileptic focus and MRI showed increased sym-
                                                                       All display various degrees of mental retardation: 4
metric T2 signals in the deep white matter in the cerebellum,
midbrain, and basal ganglia. She was treated with phenobarbital,       moderate, 2 severe, and 1 profound. All have motor
valproic acid, clonazepam, clobazam, topiramate, and lam-              disabilities: 3 are nonwalkers, 3 require aid, and
otrigine as well as a ketogenic diet and vagal nerve stimulation,      only 1 walks without assistance although her gait

                                                                       Neurology ●●●                                                   3
Table 1        Demographic and clinical characteristics of the study group

    Case                         Age at formula          Presenting
    no.       Current age        feeding, mo             symptoms                 MRI                                             Outcome

    1         5 y 3 mo             1–5                   Vomiting,                Bilateral, symmetric, increased T2 signal       Walks with aid, moderate mental retardation,
                                                         ophthalmoplegia          in the basal ganglia, mammillary bodies,        microcephaly, hypotonia, ophthalmoplegia
                                                                                  and periaqueductal grey matter

    2         5y                 0.5–3.5                 Weak cry,                Delayed myelinization and a thin corpus         Spastic quadriplegia, severe mental
                                                         aphonia                  callosum                                        retardation, microcephaly, ventilation,
                                                                                                                                  severe kyphoscoliosis

    3         5 y 3 mo           2.5–6                   Lethargy,                Increased T2 signals in the thalamus,           Walks with support, moderate mental
                                                         nystagmus                pons, and cortical regions                      retardation, left hemiparesis, strabismus

    4         5 y 3 mo           1.5–4                   Lethargy,                Increased T2 signals in the brainstem           Walks with a walker, moderate mental
                                                         encephalopathy           and mammillary bodies                           retardation, microcephaly, strabismus,
                                                                                                                                  hypotonia, dystonia

    5         5 y 4 mo             5–9                   Vomiting, vertical       Diffuse symmetric abnormalities in the          Persistent vegetative state, spastic
                                                         nystagmus                basal ganglia, brainstem, mammillary            quadriplegia, profound mental retardation,
                                                                                  bodies, and white matter                        paralysis of left diaphragm, ventilation,

    6         5y                   1–3.5                 Vomiting,                Delayed myelinization and brain atrophy         Unable to sit or stand, severe mental
                                                         diarrhea, lethargy                                                       retardation, vertical nystagmus, hypotonia

    7         6y                  10–14                  Weakness,                Normal (not in the acute stage)                 Walks independently unstable, moderate
                                                         lethargy,                                                                mental retardation, hyperactivity, short
                                                         hypotonia                                                                attention span, disinhibition, hypotonia,
                                                                                                                                  stereotypic movement of hands

                                    is unstable. Four children remain with hypotonia,                         deficiency in children has not yet been reported. In
                                    2 with spastic quadriplegia, and 1 with spastic                           one adult study, 16 out of 50 consecutive neurologic
                                    hemiparesis. One child is in a persistent vegetative                      patients with thiamine deficiency showed epileptic or
                                    state. All have various symptoms of brainstem                             epileptiform manifestations.10 The authors suggested
                                    dysfunction (swallowing difficulties, strabismus,                         a possible subclinical predisposition for seizures pro-
                                    ophthalmoplegia, nystagmus), or basal ganglia                             voked by the thiamine deficiency. There was no such
                                    dysfunction (hypotonia, movement disorder).                               indication in any of our patients.
                                    Four remain with microcephaly.                                                There are a number of possible pathophysiologic
                                    DISCUSSION      We report on the outcome of 7 chil-                       mechanisms by which thiamine deficiency may con-
                                    dren who displayed severe epilepsy after being ex-                        tribute to seizure activity. Thiamine plays a central
                                    posed in infancy to a thiamine-deficient formula. All                     role in cerebral metabolism. It serves as a cofactor for
                                    have mental retardation, motor disabilities, and                          several enzymes involved in carbohydrate catabolism,
                                    brainstem dysfunction. Data on the long-term effect                       such as pyruvate dehydrogenase complex, a key en-
                                    of children who survived infantile thiamine defi-                         zyme in the Krebs cycle.11,12 Furthermore, it has an
                                    ciency are scanty due to the high fatality rate.5 An                      important role in the biosynthesis of neurotransmit-
                                    association between persistent epilepsy and thiamine                      ters, as well as in the production of reducing equiva-

    Table 2        Seizure history and EEG abnormalities of the study group

    Case                                                   Seizure-free
    no.    Initial seizures   EEG at presentation          period, mo         Later seizures     EEG at follow-up                      Seizure outcome (current treatment)

    1      Tonic,             Slow background (right ⬎     3                  Myoclonic          Generalized spike wave                Seizure-free (ketogenic diet)
           myoclonic          left)

    2      Tonic              Slow background              1                  Myoclonic          Multifocal with secondary             Rare seizures (PB, VGB)

    3      Focal              Slow background              5                  Complex partial    Modified hypsarrhythmia               Seizure-free (VGB)

    4      Tonic,             Slow background              3                  Complex partial    Modified hypsarrhythmia,              Seizure-free (PB, VGB)
           myoclonic                                                                             multifocal

    5      Focal              Moderate to severe           3                  Focal              Hypsarrhythmia, multifocal            Infrequent seizures (VGB, TPM)

    6      Tonic,             Mild slowing (right)         7.5                Myoclonic, tonic   Multifocal spike and wave, slowing    Frequent seizures (PB, felbamate, vagal
           myoclonic                                                                             of the background                     nerve stimulation)

    7      Suspected          Not available                9                  Myoclonic          Paroxysmal spikes, polyspikes,        Rare seizures (VGB, LTG)
           focal                                                                                 and spike wave complexes

PB ⫽ phenobarbital; VGB ⫽ vigabatrin; TPM ⫽ topiramate; LTG ⫽ lamotrigine.

4                                   Neurology ●●●
lents used in oxidant stress defenses, due to its role as   important, because of the unusual event that led to
a cofactor in the pentose cycle.13 Thus, the 3 possible     isolated thiamine deficiency in infants otherwise
mechanisms for seizures might be the lack of energy         not exposed to malnutrition. Our findings indi-
production, the lack of inhibitory neurotransmitters        cate that infantile thiamine deficiency may cause
in the brain, and possible oxidative stress. Thiamine       severe epilepsy in children.
deficiency results in energy deficiency, similar to mi-
tochondrial disorders, which are known to cause             Received November 25, 2008. Accepted in final form May 18, 2009.
myoclonic seizures (as shown in 4 of our patients).
Also, the fact that the first EEGs showed background
slowing without epileptic activity supports a meta-         REFERENCES
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6   Neurology ●●●
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