Evaluation of the Child With Acute Ataxia: A Systematic Review

Pediatric Neurology 49 (2013) 15e24

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Topical Review

Evaluation of the Child With Acute Ataxia: A Systematic Review Harry T. Whelan MD a, *, Sumit Verma MD a, Yan Guo MD, PhD a, Farouq Thabet MD a, Xiuhua Bozarth MD, PhD a, Michelle Nwosu MBBS a, Akshat Katyayan MD a, Venu Parachuri MD a, Katie Spangler MD a, Barbara E. Ruggeri MLIS b, Sindhu Srivatsal MD a, Guojun Zhang MD, PhD a, Stephen Ashwal MD c a

Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin Department of Neurology, Medical College of Wisconsin Libraries, Medical College of Wisconsin, Milwaukee, Wisconsin c Division of Pediatric Neurology, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California b

article information

abstract

Article history: Received 24 May 2012 Accepted 17 December 2012

Evaluation of acute ataxia in a child poses a dilemma for the clinician in determining the extent and timing of initial screening tests. This article reviews the evidence concerning the diagnostic yield of commonly ordered tests in evaluating the child with acute ataxia. The literature revealed the following frequencies of laboratory screening abnormalities in children with acute ataxia: CT (w2.5%), MRI (w5%), lumbar puncture (43%), EEG (42%), and toxicology (49%). In most studies, abnormalities detected by these screening tests were nondiagnostic. There are insufficient data to assess yields of testing for autoimmune disorders or inborn errors of metabolism. A toxicology screen should be considered in all children presenting with acute ataxia. Neuroimaging should be considered in all children with new onset ataxia. Cerebrospinal fluid analysis has limited diagnostic specificity unless clinically indicated. Studies to examine neurophysiology testing did have sufficient evidence to support their use. There is insufficient evidence to establish a role for autoantibody testing or for routine screening for inborn error of metabolism in children presenting with acute ataxia. Finally, in a child presenting with ataxia and opsoclonus myoclonus, urine catecholamine testing for occult neuroblastoma is recommended. Nuclear scan may be considered, however, there is insufficient evidence for additional body imaging. Ó 2013 Elsevier Inc. All rights reserved.

Introduction

Acute ataxia, defined as unsteadiness of walking or of fine motor movement of <72 hours’ duration, can present acutely or subacutely in infants and children. Ataxia can be of different types, based on localization in the nervous system, including cerebellar, vestibular, epileptic, sensory, and psychogenic. Although the exact incidence is unknown, acute ataxia usually results in the need for hospitalization and extensive laboratory investigation. Parents of affected children are anxious, distraught, and * Communications should be addressed to: Dr. Whelan; Department of Neurology; Medical College of Wisconsin; 8701 Watertown Plank Rd, CCC 540; Milwaukee, WI 53226. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2012.12.005

frightened at the acute deterioration in their child’s neurologic status and typically seek early medical and neurologic evaluation. Clinicians are often faced with deciding the extent and timing of initial screening tests, particularly to detect treatable causes. This systematic review evaluated evidence concerning the diagnostic yield of commonly used tests to evaluate the previously well child with acute ataxia including: (1) neuroimaging; (2) cerebrospinal fluid (CSF) examination; (3) neurophysiologic studies; (4) toxicology screening; (5) testing for autoimmune-related disorders including occult neuroblastoma; and (6) testing for inborn errors of metabolism. The results section first considers important features related to the clinical context of the presentation of acute ataxia in children and then reviews evidence related to these screening diagnostic laboratory studies.

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Description of the analytic process

We performed a literature search (1966-2011) that resulted in 3829 abstracts, 61 of which were selected for full-text review. Appendices A and B describe the databases searched, search terms used, and the article classification scheme. Results Clinical context

Evaluation of the infant or child presenting with acute ataxia typically begins with obtaining a detailed history of the presenting illness including the onset, timing, and progression of symptoms, which may be helpful in excluding serious etiologies [1]. The most common causes of childhood ataxia include postinfectious acute cerebellar ataxia, toxin ingestion, and Guillain-Barré syndrome. Table 1 summarizes data from two class III studies that reported the etiologies of acute cerebellar ataxia in 79 children. A history of fever, antecedent respiratory, gastrointestinal, and varicella or Epstein-Barr virus infections may suggest a postinfectious etiology. A history of recent vaccinations or exposure to toxins, alcohol, drugs, or household medications and chemicals commonly provide information suggesting a specific diagnosis. A family history of similar or recurrent symptoms as well as a personal or family history of seizures or migraine headaches may additionally suggest a metabolic or genetic disorder. Recent head or neck trauma can present with ataxia and may be due to vertebrobasilar dissection or intracranial bleeding. Ataxia may be present after ingestion of lead, alcohol, anticonvulsants, benzodiazepines, antihistamines, organic chemicals, or heavy metals. A retrospective study provided class III evidence that 32.5% of acute ataxia in children is caused by ingestion regardless of whether a history of toxin exposure is elicited [2]. In this study, 49% of toxicology screens were positive. Examination also may reveal fever or meningismus, which may be indicative of a central nervous system (CNS) infection. Pharyngitis, lymphadenopathy, and splenomegaly occur in Epstein-Barr virus infection. Otoscopic (otitis media) and skin (viral exanthema) examination may also help with diagnosis.

Neurologic evaluation is of high diagnostic yield. The presence of papilledema in the setting of headaches, emesis, and diplopia suggests raised intracranial pressure. Urgent neuroimaging may reveal hydrocephalus, posterior fossa tumors, or developmental nervous system abnormalities (e.g., Arnold-Chiari or Dandy-Walker malformation). Bradycardia, hypertension, and papilledema may be indicative of raised intracranial pressure. Changes in mental status may occur in toxin ingestion, acute disseminated encephalomyelitis, seizures, CNS infections, structural abnormalities, or hemorrhage. Visual motor or optic ataxia is described as impaired visual control of the direction of the arm reaching for a visual target, resulting in defective hand orientation and grip formation. It may be associated with lesions in the superior parietal lobule, which also affects visual-guided saccades and other forms of eyeehand coordination [3]. Vestibular causes of ataxia are also common. Benign paroxysmal positional vertigo is characterized by sudden onset of vertigo provoked by change in the position of head associated with gait imbalance [4]. Benign paroxysmal vertigo is a periodic syndrome thought to be migraine equivalent in children and is more common than benign paroxysmal positional vertigo [5]. Diagnosis is by detailed history with special emphasis on family history of periodic disorders like migraine and neuro-otologic examination, including the Dix-Hallpike test. Electronystagmography and videonystagmography help to differentiate between vestibuloplasty and benign paroxysmal positional vertigo as a cause of vertigo [6]. Cranial nerve abnormalities may be present in posterior fossa disease and ophthalmoplegia in Miller Fisher syndrome. Opsoclonus or myoclonus occurs in the opsoclonus-myoclonus syndrome, a paraneoplastic disorder associated in many children with occult neuroblastoma that can be diagnosed with chest or abdominal computed tomography (CT) and metaiodobenzylguanidine (MIBG) scans. Cerebellar lesions may present with intentional tremor, hypotonia, titubation, or nystagmus and speech, coordination, and gait abnormalities. Weakness and loss of reflexes are found in Guillain-Barré syndrome and Miller Fisher syndrome. Sensory ataxia may be a sign of dorsal column dysfunction with loss of proprioception characterized by a positive Romberg sign and decreased reflexes and can be seen in children with Guillain-Barré syndrome, acute disseminated encephalomyelitis, and multiple sclerosis.

Table 1. Etiologies of acute ataxia in 79 children

Author/Year [Ref]*

No. of Patients

Postinfection

GBS

Toxin

ADEM

Martínez-González et al., 2006 [12] Gieron-Korthals et al., 1994 [2] TOTAL

39 40 79

20 14 34

1 5 6

10 13 23

1 1

S/D

1 1

PF Tumor

0

NB

TBI

1

2

1

2

Infection

Misc.y

BPV

Functional

2 2

2 3 5

1 1 2

1 1 2

Abbreviations: ADEM ¼ Acute disseminated encephalomyelitis BPV ¼ Benign positional vertigo GBS ¼ Guillain-Barré syndrome NB ¼ Neuroblastoma PF tumor ¼ Posterior fossa tumor S/D ¼ Stroke/dissection * These two studies were class III. y Miscellaneous etiologies in the Martinez-Gonzales et al. paper (2006) included two patients with recurrent vertigo and in the Gieron-Korthals et al. paper (1994), etiologies included one patient each with myositis and Reye syndrome. As for defined infection, in the Martinez-Gonzales et al. paper (2006), the etiology was determined in 95% (19 of 20) of the patients: chickenpox (10), unspecified virus (6), mycoplasma (1), enterovirus (1), and Epstein-Barr virus (1).

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testing, chromosomal microarray, serum lactate, pyruvate, carnitine, acylcarnitine, vitamin E and amino acid determinations, urine organic acid screening, and testing for fragile X syndrome.

A psychogenic or nonorganic cause of ataxia should be considered when the examination findings are bizarre, inconsistent, or incongruent. Further history may reveal a previous psychiatric illness, secondary gain, or a precipitating event [7]. In a 1991 study by Lempert et al. [8], certain features of psychogenic disorders of stance and gait were described, including fluctuation of impairment, excessive slowness of movement, “walking on ice,” uneconomic posture with wastage of muscular energy, and sudden buckling of knees. A diagnosis of psychogenic ataxia would be one of exclusion. On occasion children present with acute ataxia, but in fact they have subtle chronic ataxia that was precipitated by an acute stressor such as infection. In such individuals, consideration of causes of chronic ataxia must be considered. A recent class II study found that specific risk factors were helpful in differentiating acquired (i.e., noninherited) from inherited etiologies of subacute or chronic childhood ataxia [9]. These risk factors included (1) duration of symptoms >2 weeks; (2) consanguinity; (3) a first-degree relative with similar presentation; (4) presenting symptoms of abnormal gait, rash, ichthyosis, or multiorgan abnormalities; and (5) abnormal examination findings of motor function (gait, tone, strength), deep tendon reflexes, and clonus, dysmetria, pes cavus, or sensory deficits. The presence of these risk factors suggested a greater likelihood of a genetic or metabolic disorder that frequently could be determined by specific testing including mitochondrial DNA

Evidence Diagnostic yield of neuroimaging in children with acute ataxia

Four class III studies of 172 children aged <17 years with acute ataxia were reviewed (Table 2) [2,10-12]. The majority of individuals were studied retrospectively [2,10,11], with only one series reporting prospective data [12]. GieronKorthals et al. [2] and Martínez-González et al. [12] defined acute ataxia as symptoms for <48 hours in a previously healthy child; however, in the studies performed by Connolly et al. [10] and Nussinovitch et al. [11], the ataxia onset ranged from 9.9  7.9 to 8.8  7.4 days. The majority of cases of ataxia were postinfectious (78% [2], 52% [12]) or caused by drug ingestion (32.5% [2], 25.6% [12]) or Guillain-Barré syndrome (12.5% [2]). Neuroimaging (81 CT; 20 magnetic resonance imaging [MRI]) was acquired in 56.4% (97 of 172) of patients. Two patients had abnormal CT scans (2.5%, cerebellar infarct and increased T2 changes), and one patient had an abnormal MRI study (5%, increased T2 signal in left cerebellar hemisphere). Another group of studies examined specific neurologic disorders that commonly presented with acute ataxia in children. For these conditions, neuroimaging was

Table 2. Diagnostic yield of CT and MRI in children with acute ataxia

Author/Year [Ref]

No. of Patients With NI/Total No. of Patients

Mean Age (yr)

Class

No. of Patients Who Had CT/MRI

CT (No. of Patients With Abnormal CT/ All Patients With CT)

MRI (No. of Patients With Abnormal MRI/ All Patients With MRI)

Comments

Martínez-González et al., 2006 [12]

13/20

4.6

III

13/4

0/13

0/4

Gieron-Korthals et al., 1994 [2]

20/40

0-6 (60%) 7-12 (25%) 13-18 (15%)

III

19/7

2/19

2/7

Connolly et al., 1994 [10]

52/73

5.4

III

37/9

0/37

1/9

Nussinovitch et al., 2003 [11]

12/39

4.8

III

12/0

0/12

0/0

Acute ataxia defined as acute ataxia for <24 hr with no previous illnesses 20/39 patients diagnosed with postinfectious acute ataxia; the rest had other causes of acute ataxia Acute ataxia defined as the acute onset of ataxia over 1-2 days with/without a history of preceding viral illness and without fever or seizures 35% of patients had postinfections acute ataxia 2 patients with abnormal MRId1 had cerebellar infarct and 1 had cerebral edema with Reye syndrome Acute ataxia defined as an acute disturbance in gait and balance that may develop after a wide variety of illnesses 46 had CT or MRI and the rest had nucleotide studies or PEG. The 1 patient with abnormal MRI had inc T2WI in left cerebellar hemisphere. Acute ataxia defined as the sudden onset of ataxia following an infectious illness, usually viral

Total

97/172

81/20

2/81

1/20

Abbreviations: CT ¼ Computed tomography MRI ¼ Magnetic resonance imaging PEG ¼ Percutaneous endoscopic gastrony T2WI ¼ Increased T2-weighted resonance

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frequently critical for making a specific diagnosis (e.g., acute disseminated encephalomyelitis, posterior fossa tumor, posterior circulation stroke, head injury, etc.). Data from five class III studies of 84 children and adults with acute disseminated encephalomyelitis found that acute ataxia was the presenting feature in 52% of individuals, and 86% had an abnormal MRI [13-16]. However, a study performed by Pavone et al. [17] on 17 children with acute disseminated encephalomyelitis using different modalities of imaging (CT, MRI [0.5, 1.5T] with and without contrast) showed 100% of patients to have more than three white matter lesions at the onset of symptoms. In one study of 18 acute disseminated encephalomyelitis patients, MRI was abnormal in 55% of patients who presented with acute ataxia, whereas CT was abnormal in only two patients [13]. In two class III studies totaling 78 patients with posterior fossa tumor, 54% presented with ataxia [18,19]. Of 38 children with astrocytomas, 56% presented with ataxia, and all children had an abnormal CT scan [18]. A study of 40 children aged 0 to 3 years with ependymoma found that 53% presented with ataxia and all had abnormalities detected by either CT or MRI [19]. The mean duration of ataxia in these young children prior to the diagnosis of brain tumor was reported to be 50 days [19]. Posterior circulation strokes, although rare in children, can present with acute ataxia. In one class III study [20] including 68 pediatric patients with vertebral artery dissection, 36 (53%) had acute ataxia. Cerebral angiography was performed in 63 (92.6%) cases with abnormalities in the left vertebral artery in 36 (57.1%), right vertebral artery in 20 (31%), and bilateral in 7 (11.1%). The most common site of abnormality was identified in the V2 segment (C1-C6) of the vertebral artery. The CT was abnormal in 94% of the patients (31 of 33) and normal in two patients. MRI in 22 patients detected infarction in 95% and was normal in one patient. Magnetic resonance angiography performed for 13 patients were all abnormal. CT angiography was abnormal in all 63 patients in whom it was performed. In one class III study including 311 children with head trauma, acute ataxia was the presenting feature in 5% [21]. Nine of these 14 patients with ataxia underwent CT scanning, which was abnormal in five cases. One class III study described enterovirus-71 encephalitis in 41 children; 21 (52%) had acute ataxia [22]. In this study, brain MRI performed for 46% of patients showed brainstem lesions in 71% of these patients. Conclusions. The yield of brain neuroimaging in children with postinfectious acute ataxia is low (CT w2.5%; MRI w5%). For specific neurologic disorders, it is much higher with the likelihood of detecting an abnormality depending on the underlying etiology and which imaging modality was used. In four class III studies of patients with acute disseminated encephalomyelitis, MRI showed abnormalities in 86% of patients in contrast to CT, which was abnormal in only 11% in one class III study. As expected, patients in whom ataxia was a prominent presenting feature and who were diagnosed with a posterior fossa tumor had abnormal imaging in all patients (two class III studies). In one class III study with posterior circulation stroke due to vertebral artery dissection, the yield was 94%, 95%, and 100% for CT, MRI, and computed tomography angiography, respectively. In one

class III study of enterovirus encephalitis, brain stem lesions were detected on MRI in 71% of the patients. Clinical context. Although the diagnostic screening yield of CT

and MRI is low (Table 2), the data in Table 1 indicate that in 5% (4 of 79) of children initially being evaluated for ataxia, a specific diagnosis such as tumor, stroke, or acute disseminated encephalomyelitis can only be made with neuroimaging. Many children are subsequently not considered to have acute ataxia as this frequently is implied to mean that the etiology is not postinfectious but rather ataxia secondary to a specific structural, metabolic, or infectious disorder. Because of this conundrum, it is common practice for clinicians evaluating a child with ataxia to perform an imaging study early in the diagnostic evaluation to exclude one of these conditions. Also, because of the risk of postlumbar puncture herniation in children who have a posterior fossa mass, physicians typically will perform an imaging study prior to performing a lumbar puncture to avoid this risk. Diagnostic yield of CSF studies in the children with acute ataxia

Data from six class III studies of 195 children with acute ataxia, all aged <18 years, that reported CSF results are summarized in Table 3 [2,10-12,23,24]. Ataxia was present from 1 to 12 days, and lumbar puncture, performed in 89%, was considered abnormal in 43.4% of children (range, 3365%). In the majority of studies, the leukocyte count was mildly elevated (usually <20-50 cells), predominantly lymphocytic, and the CSF protein was either normal or mildly elevated. In one study, CSF was analyzed according to the suspected etiology (e.g., viral, vaccine-related, idiopathic, etc.) and no significant differences were noted [10]. In this study, the CSF protein concentration was higher in children with neurologic signs other than ataxia (mean, 32  19 mg/dL). In these studies the mild pleocytosis was considered nondiagnostic but suggested an infectious (usually viral) or postinfectious process. In two studies, children with higher CSF protein levels (>40 mg/dL) tended to be in subgroups labeled as “nonvaricella” postviral disease and often had other signs or symptoms in addition to ataxia [10,11]. Conclusions. Data from six class III studies of 195 children with acute ataxia found abnormal CSF findings in 43% of children undergoing lumbar puncture. CSF studies showed mild pleocytosis and variable elevations of protein. Clinical context. CSF examination is frequently performed in the evaluation of children with acute ataxia. To date, the findings suggest very limited diagnostic specificity. Recent data suggesting that there are an increasing number of children being diagnosed with antineuronal antibody encephalitides raise the question whether such testing on CSF might be worth acquiring in children who present with acute ataxia. Diagnostic yield of neurophysiologic studies in children with acute ataxia

Two class III studies reported electroencephalographic (EEG) findings in 24 of 57 children with acute ataxia [11,24]. In the class III study from Nussinovitch et al. [11], 12 of 39

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Table 3. Diagnostic yield of CSF in children with acute ataxia

Author/Year [Ref]

No. of Patients

Mean Age (yr)

Class

No. of Patients Who Had LP

No. of Patients With Abnormal CSF (%)

Connolly et al., 1994 [10]

73

5.37  4.00

III

69

34 (49.3%)

Gieron-Korthals et al., 1994 [2] Nussinovitch et al., 2003 [11]

40

0-18

III

25

7 (28%)

39

4.8  3.8

III

39

19 (49%)

Siemes et al., 1981 [23]

25

1.5-15

III

25

10 (40%)

Weiss & Carter, 1959 [24]

18

1-13

III

15

5/15 (33%)

Martínez-González et al., 2006 [12]

39

4.6

III

17

65%

Total

195

173

Study Criteria for Acute Ataxia

CSF Findings

Varied depending on the etiology (i.e., viral, vaccine-related, idiopathic)

Varicella: WBC 17  26; protein 21  13 Viral: WBC 14  23; protein 31  25 EBV: WBC 0; protein 36 (1) Vaccine: WBC 2  1; protein 29  11 (2) Idiopathic: WBC 7  9; protein 21  12 (14) WBC 12-75 mm3

Acute onset ataxia over 1-2 days Acute onset (not defined in number of days or weeks) of ataxia with or without nystagmus Acute onset of truncal and gait ataxia several days to several weeks after a nonspecific infectious illness or exanthema Rapid deterioration of gait over weeks to 3 months, tremors more commonly in head and trunk, or abnormality of extraocular eye movements Acute loss of coordination or sudden onset of difficulty of walkingdwith or without associated nystagmusdduration of at least 48 hours, all of this in a previously healthy child

WBC 16.2  9.8 mm3 Protein 20.8  26.2 mg/dL Protein 410-900 mg/L

WBC 7-25 lymphocytes Protein, glucose normal

CSF WBCs ranged from 7-500

75 (43.4%)

Abbreviations: CSF ¼ Cerebrospinal fluid EBV ¼ Epstein-Barr virus LP ¼ Lumbar puncture WBC ¼ White blood cell count

children with acute ataxia had EEGs, and the EEGs were abnormal in six children (50%), four with diffuse slowing and two with epileptiform abnormalities, neither of whom had clinical seizures. No correlation with acute clinical laboratory data or long-term outcome was made. In their study, Weiss and Carter [24] reported 12 of 18 children had EEGs; four showed diffuse slowing and eight were normal. There was no correlation with the occurrence of epilepsy or severity of the ataxia with the EEG findings. Those children who remained symptomatic for >6 months were more likely to have had an abnormal EEG. A single class III study using nerve conduction and needle electromyography studies on 18 patients with acute onset polyneuropathy (suspected Guillain-Barré syndrome) of <4 days duration was included [25]. Electrodiagnostic studies found 33% (n ¼ 6) of the cohort fulfilled neurophysiologic criteria for acute inflammatory demyelinating polyneuropathy or axonal Guillain-Barré syndrome. Conclusions. Data on 24 children with acute ataxia showed

nonspecific EEG abnormities in 42%. None of the patients had clinical seizures, and in one study the children who had persistent symptoms for >6 months were more likely to have had an abnormal EEG. Very early (<4 days) electromyography (EMG) assessment in Guillain-Barré

syndrome may be nondiagnostic; however, testing multiple motor and sensory nerves (3) may detect abnormal findings suggestive of disease. Clinical context. Acute ataxia may be present during the ictal

or postictal phase of seizures in children [1]. Nonconvulsive epileptiform states have also been referred to as pseudoataxia and may present as ataxia with or without alteration of consciousness [26,27]. In such children there may be a personal or family history of epilepsy or accessibility to anticonvulsants and commonly serum or urine drug screens are performed to evaluate for drug toxicity [2,28]. Also, in children with acute ataxia, clinicians frequently consider obtaining an EEG if there is a history of epilepsy or evidence of an altered mental status or clinical suspicion of nonconvulsive epilepsy status. Nonconvulsive seizures are usually seen with pre-existing seizure disorders and cognitive impairment. This diagnosis is associated with EEG abnormalities with dramatic clinical and electrographic improvement when treated appropriately. Several studies have reported on EEG findings in children who present with both seizures and ataxia. One class III study (n ¼ 22) described electrographic abnormalities with pseudoataxia including multifocal slow, sharp, and spike waves [27]. In this study, children had pre-existing

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Table 4. Diagnostic yield of toxicology screening in children with acute ataxia

Author/Year [Ref]

No. of Patients

Age

Class

No. of Patients Who Had Toxicology Screen

No. of Patients With Positive Toxicology/ No. of Patients Who Had Toxicology Performed

Comments

Wiley & Wiley, 1998 [29]

46

14-127 mo

III

32

16/32 (50%)

Gieron-Korthals et al., 1994 [2]

40

<6 yr

III

35

17/35 (49%)

Alprazolam in 4, triazolam and temazepam in 2, diazepam and lorazepam in 1 child Children with negative toxicology screen had positive history of clonazepam or lorazepam ingestion Benzodiazepine in 5, phenytoin in 3, phenobarbitone in 3, carbamazepine in 2, and phenothiazine in 1 child

Total

86

49%

neurologic symptoms and most had a history of epilepsy. Data have also been reported in children with other conditions such as acute disseminated encephalomyelitis. A retrospective class III study (n ¼ 18) in children with acute disseminated encephalomyelitis yielded abnormal EEGs with high amplitude slow waves in 42% of cases reflecting a nonspecific encephalopathy state. EMG and nerve conduction velocity study should be considered in evaluation of acute onset ataxia in cases where clinical diagnosis of Guillain-Barré syndrome is suspected. Early neurophysiologic changes can be detected with detailed electrodiagnostic studies. Diagnostic yield of toxicology screening in children with acute ataxia

Data from two class III studies of 86 children were evaluated [2,29]. Of the total number of individuals, 67 had toxicology testing performed, and testing was positive in 49%. Agents responsible for positive screening are listed in Table 4. Specific pharmacologic agents have a high incidence of causing acute ataxia in children. Two class III studies reported benzodiazepines as a common cause of ataxia. Pulce et al. [30] found 34% of 482 children younger than 16 years of age had acute poisoning from benzodiazepine derivatives, including ethyl loflazepate, flunitrazepam, triazolam, or prazepam. Wiley and Wiley [29] described ataxia in 87% of 46 children aged 14-127 months who were hospitalized for benzodiazepine ingestion. Lorazepam (28%) was the most commonly reported drug, followed by clonazepam (20%), alprazolam (13%), and diazepam (11%). The selective central a2-adrenergic agonist agent brimonidine, which is chemically similar to clonidine and used as eye drops in the treatment of glaucoma and ocular hypertension, especially postoperatively, has also been reported in a class III study of 413 children to cause ataxia in 4.5% of cases of ingestion [31]. Isopropanol (found in rubbing alcohol) ingestion has been shown to cause ataxia in 5% of 91 children <6 years of age [32]. Altered mental status was observed in 3%. Isopropanol levels were obtained in 30% and toxic levels noted in three patients; all had altered mental status. Clinical evidence of toxicity developed between 0.5 and 2 hours’ postingestion. Conclusions. Data from two class III studies of 86 children with acute ataxia found that 67 children had screening toxicology testing performed and that 49% tested positive for drug ingestion.

Clinical context. Ataxia commonly follows ingestion and most

commonly is due to medications and less often from exposure to organic chemicals, solvents, and heavy metals. Accidental poisoning in children <6 years of age is the most common form of toxic ingestion, with a second peak in adolescence where intoxication occurs as a result of substance abuse [2]. A high index of suspicion should always be maintained, because a history of ingestion or exposure might not be forthcoming. After ingestion, ataxia is often accompanied by mental status changes such as lethargy, confusion, inappropriate speech, or unconsciousness. Clinical examination may show axial or appendicular ataxia, dysmetria, nystagmus, or positive Romberg sign. Toxicology screens are therefore commonly performed in the initial evaluation of acute ataxia in children. Other agents associated with ataxia in children include phencyclidine [33] and other recreational drugs [34,35], antiepileptic drugs [28,36-38], anticholinergic agents [39], muscle relaxants [40], mushrooms [41], and cold remedies [42]. Diagnostic yield of testing for immune disorders in children with acute ataxia: Neuroblastoma

Neuroblastoma is a rare cause of acute ataxia, reported in only one of 191 patients from four class III studies (Table 1). However, as discussed in the clinical context section below, ataxia is a common manifestation of neuroblastoma, especially when it presents as the initial symptom in the opsoclonus-myoclonus syndrome. MIBG scintigraphy. Four class III studies (n ¼ 441) reported

sensitivity or specificity data on the use of MIBG scintigraphy in patients suspected of having neuroblastoma (Table 5) [43-46]. Sensitivities ranged from 70% to 92%. One study detected residual, recurrent, or metastatic neuroblastoma in 16 of 20 patients (80%) [43]. Another study showed MIBG sensitivity of 70% in detecting abdomen or pelvic neuroblastoma and 83% in detecting thoracic neuroblastoma [45]. In a third study, sensitivity differences between iodine-131 MIBG and iodine-123 MIBG were not observed.[46]. Imaging. In one class III study, there were 21 patients with neuroblastoma, with tumor location being thoracic in seven patients and abdominal or pelvic in 14 patients. Five thoracic cases and 10 abdominal or pelvic cases had MRI or CT, which showed a 100% detection rate [45]. Also observed was a diagnostic sensitivity of 71% (five of seven patients) for

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Table 5. Role of MIBG scan and other screening tests for occult neuroblastoma

Study

N

Mean Age

Class

Sensitivity/Specificity

97 20 101 196

6 mo to 12 yr 18/20 children Unclear 8 mo to 65mo

III III III III

84%/100% 95%/96% 70%/83% 92%/100%

Unclear

III

100%/100%

3 wk first screen; 6 mo second screen 6 mo

I

39%/87-100% (histology not available in 4 cases) 37%/presumed 100%

MIBG Claudiani et al., 1995 [46] Hoefnagel et al., 1987 [43] Brunklaus et al., 2012 [45] Biasotti et al., 2000 [44] MRI/CT Brunklaus et al., 2012 [45] Urine catechol-amines Takeuchi et al., 1995 [47]

Population based

Yamamoto et al., 1995 [48]

Population based

21

I

Abbreviation: MIBG ¼ Metaiodobenzylguanidine

detecting thoracic neuroblastoma by chest x-ray and an 89% detection rate for abdominal involvement using ultrasound. Urine catecholamines screening. In a large population-based

study (Quebec Neuroblastoma Screening Project), screening for neuroblastoma was performed on 340,000 infants at 3 weeks of age and 245,000 infants at 6 months of age. The tumor detection rate was similar to the detection rate through clinical examination (31 vs 48). In fact, 27 infants, in whom screening was negative, were diagnosed clinically [47]. In a mass screening for neuroblastoma performed in Japan, although an increased incidence of this tumor was noted in infants younger than 1 year old, there was no significant decrease in overall mortality [48]. Two class I screening studies on infants showed increased detection rates of 65% and 39%, respectively [47,48]. One class III study showed a 24% (five of 21) detection rate by urine catecholamines [45]. In one class III study, 16 of 196 patients with neuroblastoma had false-negative MIBG, and vanillylmandelic acid (VMA) urinary excretion at the time of diagnosis was within physiological values in 13 of 16 patients; urinary homovanillic acid (HVA) levels were also normal in seven patients [44]. In another class III study, only 37 of 408 (9%) had elevated urinary HVA or VMA levels, and neuroblastoma was subsequently diagnosed [49]. In three additional patients with normal HVA and VMA levels, tumors were subsequently diagnosed (false-negative rate of 7.5%). Ten percent of the patients with neuroblastoma had normal HVA and 27.5% had normal VMA levels at the time of diagnosis. More than 60% of the patients with neuroblastoma had urinary HVA or VMA levels higher than twice the upper limit of normal. No false-positive results were encountered. Conclusions. Data from 191 children with acute ataxia found

that neuroblastoma occurred in w0.05%. Four class III studies found diagnostic yields of MIBG scintigraphy ranging from 70% to 92% in detecting primary tumor. Data from one class III study demonstrated very high sensitivity of MRI and CT in detecting neuroblastoma. Two class I studies (detection rate 37% and 65%) and three class III studies (detection rate 9-24%) showed increased detection rates of neuroblastoma using measurement of HVA and VMA, but the rate of detection was not higher than tumors detected clinically with no overall decrease in mortality.

Clinical context. Opsoclonus-myoclonus syndrome is a rare

autoimmune disorder in which neuroblastoma is found in at least 50% of affected individuals [50]. Acute ataxia is usually the first presenting symptom frequently followed by eye findings of opsoclonus (erratic, nonrhythmic dancing movements of eye) and myoclonus. Although some children with opsoclonus-myoclonus syndrome test positive for paraneoplastic or antineuronal autoantibodies, there are no reports in which these antibodies have been detected when acute ataxia occurs without opsoclonus-myoclonus syndrome developing [51-53]. Detecting the presence of neuroblastoma requires CT or MRI, bone and MIBG scans, bone marrow testing, urine catecholamine measurements, and other studies (Table 5). According to the pediatric neuroblastoma practice guidelines from the 1996 National Comprehensive Cancer Network, the diagnosis of neuroblastoma is based on (1) characteristic histopathology findings or (2) the presence of bone marrow tumor-cell clumps or syncytia in conjunction with elevated levels of one or more urinary catecholamine metabolites [54]. VMA and HVA are the most common catecholamines examined. Diagnostic yield of testing for other autoimmune disorders: Disorders associated with the presence of autoantibodies

Autoimmune disorders are believed to play an important role in acute ataxia. Testing performed to screen for autoimmune disorders include examination for the presence of antinuclear antibodiesdanti-SS-A/Ro and anti-SSB/Ladanticardiolipin antibody, and antiphospholipid antibodies. However, there are no class I to III studies that have systematically examined their role. Celiac disease. Celiac disease occurs in 0.4-1.3% of children and can be associated with neurologic symptoms. Adults with celiac disease can develop acute ataxia, presumably because of cross-reactivity of antigliadin antibodies and Purkinje cells. However, two class III studies totaling 862 children [55,56] found no cases presenting with acute ataxia. acid decarboxylase. Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for the synthesis of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. It is selectively expressed in GABAergic neurons and in pancreatic b cells. GAD is a major

Glutamic

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autoantigen in type 1 diabetes mellitus, and autoantibodies to GAD (GAD-ab) are detected in about 80% of newly diagnosed type 1 diabetes mellitus patients. GAD-ab is a nonparaneoplastic antibody associated with a spectrum of neurologic syndromes [57], including stiff person syndrome, cerebellar ataxia, epilepsy, idiopathic limbic encephalitis, and myasthenia gravis. There were no studies that have examined the association of GAD in children with acute ataxia. Conclusions. There are insufficient data to draw any conclusions regarding the diagnostic yield of screening testing of autoimmune disorders in children presenting with acute ataxia. Data from two class III studies suggest that acute ataxia is unlikely to occur in children with celiac disease. There are insufficient data regarding the role of GAD-ab in childhood acute ataxia. Clinical context. Physicians commonly order selected tests to

evaluate children with acute ataxia for an underlying immune-mediated disease. Several case reports have been published that document the presence of these autoantibodies as a rare cause of acute ataxia [58-62]. There are additional reports of other antineuronal antibodies in children with acute ataxia, including antimyelin-associated glycoprotein [63], glutamate receptor delta-2 autoantibody [64], and postvaricella anticentrosomal antibodies [65]; however, their role as a cause of acute ataxia remains to be determined. Diagnostic yield of screening for inborn errors of metabolism in children with acute ataxia

There are only class IV data regarding diagnostic testing for diseases of inborn errors of metabolism in children with acute ataxia. Conclusions. There are no data to draw any conclusions regarding the diagnostic yield of routine screening testing for inborn errors of metabolism in children presenting with acute ataxia. Clinical context. Inborn errors of metabolism may present as

episodic or chronic ataxias often accompanied by epilepsy and motor or cognitive impairments. On occasion and early during disease progression, symptoms of these disorders may mimic acute ataxia. Several inborn errors of metabolism have been described in which ataxia is an early and prominent feature and include glucose transporter-1 deficiency syndrome, pyruvate dehydrogenase deficiency, and biotinidase deficiency [66-69]. Other inborn errors of metabolism that have been associated with the early appearance of ataxia include maple syrup urine disease and Hartnup disease. Disorders affecting mitochondrial function are also well known to have ataxia as an early and prominent symptom. Conclusions

In summary, although many causes of acute ataxia are benign, patients with life-threatening processes must be quickly identified. Clinical manifestations and selected ancillary testing can identify conditions requiring stabilization and intervention, as listed below. These

recommendations are based on consensus of the authors’ panel after this systematic review was completed. It is clear that there is a compelling need for large prospective studies to address the diagnostic yield of these tests.  Toxicologic screen: A urine drug screen or blood for specific drug levels (as suggested by the history) may be the most useful diagnostic test for children with acute ataxia. In a retrospective review of 40 cases of acute childhood ataxia evaluated in the emergency department at one institution, nearly half of the 35 drug screens sent were positive (Table 4).  Metabolic evaluation: For children with episodic acute ataxia and other features that suggest an inborn error of metabolism (such as altered mental status or family history), the following tests may be useful: liver function tests, blood pH, hemogram, quantitative amino acid determinations of blood and urine, serum lactate, pyruvate and ammonia levels, and urine organic acids.  Cerebrospinal fluid examination: CSF should be obtained whenever there is concern for CNS infection, such as meningitis or encephalitis. Otherwise, CSF examination is rarely indicated for the emergent evaluation of a child with acute ataxia. Moderate CSF protein elevation can occur in acute cerebellar ataxia, acute disseminated encephalomyelitis, and multiple sclerosis. CSF protein is also usually elevated in Guillain-Barré syndrome, but it may be normal in as many as 20% of children within a week of symptom onset. Neuroimaging should be obtained before a lumbar puncture is performed when there is concern for increased intracranial pressure.  Imaging: Neuroimaging should be obtained for patients with acute ataxia who have altered levels of consciousness, focal neurologic signs, cranial neuropathies, marked asymmetry of ataxia, concern for a mass lesion, or a history of trauma. Imaging may also be helpful when considering a diagnosis of exclusion, such as acute cerebellar ataxia or a conversion disorder. MRI is the imaging modality of choice for patients with acute ataxia, although MRI may be difficult to obtain emergently. It is superior to CT for detection of posterior fossa lesions such as tumors, strokes, and abscesses. In addition, patients with demyelinating diseases or brainstem encephalitis may have abnormalities detected with MRI. CT is generally more available emergently than MRI. CT can usually detect conditions that require immediate surgical intervention such as hydrocephalus, traumatic injury, and many mass lesions.  Electrophysiologic studies: Electrophysiologic studies are rarely necessary for the evaluation of acute ataxia. In consultation with a pediatric neurologist, EEG is indicated for children who may be having seizures, as suggested by altered levels of consciousness or fluctuating clinical signs. EEG may also demonstrate nonspecific abnormalities that are clues to a metabolic etiology or toxic exposure. Although electrophysiologic studies are the most specific and sensitive tests for diagnosis of Guillain-Barré syndrome, they may not be helpful early in the disease.  Specific evaluations: Evaluation for occult neuroblastoma should begin in children whose acute ataxia does not begin to resolve within 2 weeks.

H.T. Whelan et al. / Pediatric Neurology 49 (2013) 15e24 This work was supported by the Bleser Endowed Chair in Neurology and Baumann Research endowment to Dr. Whelan. We thank Debbie Dye for administrative support.

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Appendix A: Description of literature search and review of relevant articles

Literature searches of MEDLINE and Embase were conducted for relevant articles published from 1965 to September 2011 using the following keywords: ataxia, magnetic resonance imaging, tomography, x-ray computed, CT scan or cranial CT, lumbar puncture, spinal puncture cerebrospinal fluid, spinal tap, cerebrospinal fluid pressure, cerebrospinal fluid proteins, blood chemical analysis, blood cell count or CBC, hematologic tests, blood specimen

collection, blood culture, bacteriological techniques, liver function tests, EEG, electroencephalography, EMG, electromyography, heavy metal screening, toxicology, toxicology tests, substance abuse detection, toxicology screening, neurotoxicity syndromes, heavy metal poisoning, nervous system, heavy metal, poisoning, autoimmune diseases serologic tests, serologic tests, C-reactive protein, blood sedimentation, ESR, autoantibodies (antinuclear antibodies), ANA, immunologic tests, metabolic diseases, screening for inborn errors of metabolism, inborn errors of metabolism, amino acids, amino acid test, 3iodobenzylguanidine, metaiodobenzylguanidine, MIBG scan, paraneoplastic syndrome, neuroblastoma, catecholamines, homovanillic acid, HVA, vanillylmandelic acid, VMA, screening, diagnostic imaging, abdomen, abdominal imaging, pelvis, pelvic imaging, chest, and thorax. Approximately 3829 abstracts were reviewed for content regarding the establishment of the etiology of ataxia. Abstracts were reviewed and case series or reports with less than 10 patients were excluded. Foreign language reports were excluded except for one article we identified in our search for references. This article we had translated. From these abstracts, 61 articles were reviewed. Each article was reviewed and classified by two author panel members. Data reviewed included first author, year, study population, study design, number of patients, and results of testing. A four-tiered classification scheme for determining the yield of established diagnostic and screening tests developed by the American Academy of Neurology was utilized as part of this parameter [70] (Appendix B). The “screening” rather than “diagnostic” classification of evidence scheme was used for this guideline because we were determining the diagnostic yield of testing in situations in which the diagnosis of acute or new onset ataxia was already established. The diagnostic classification scheme is used when determining if a specific test can diagnose a disease process. Appendix B: Classification of evidence for rating of a screening article

Class I: A statistical, population-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients’ clinical presentations. Class II: A statistical, nonreferral clinic-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients’ clinical presentations. Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician. Class IV: Expert opinion, case reports, or any study not meeting criteria for classes I to III.