Case 1: The importance of a complete history

A 10-month-old Cree boy from northern Quebec presented to his family doctor with a three-day history of rhinorrhea, cough and fever. He had presented to the clinic with these symptoms on each of the two previous days and was sent home with a diagnosis of viral upper respiratory tract infection. His appetite had decreased, he was described as “cranky” and he had vomited once. There were no ill contacts. He had been a healthy child apart from some gastroesophageal reflux, for which he was taking domperidone and ranitidine. On physical examination, he had a low-grade fever (38.2°C), a pulse of 150 beats/min and a respiratory rate of 40 breaths/min, with an oxygen saturation of 94% in room air. He looked unwell and was irritable, but his physical examination was nonspecific apart from mild intercostal retractions. On investigation, his white blood cell count was 13.3×109/L (normal range 6×109/L to 17.5×109/L), with 34% neutrophils, and his chest x-ray was suggestive of a mild left lower lobe pneumonia. He was admitted and treated with intravenous antibiotics. He initially seemed to improve with the intravenous fluids and antibiotics. On the second day of his admission, his grandparents, who spoke better English than his mother, provided some additional information. They had witnessed his “eyes rolling back” or “wandering” over the past few weeks and thought that he had decreased activity and shown some vague behavioural changes over the past month. Around this time, his eyes were noted to intermittently roll back in his head, with some tremors and stiffness of his lower extremities. On the third day of his hospitalization, he deteriorated rapidly, becoming very spastic and poorly responsive, with a tonic-clonic convulsion. He was given phenobarbital and phenytoin and intubated for transport to a tertiary care centre. At the tertiary care centre, the patient remained intubated and sedated, and continued on his antibiotics and anticonvulsants. A further test was performed, which revealed the diagnosis. A further history obtained at the tertiary care hospital from the maternal grandparents revealed that a maternal uncle had a child with a similar clinical presentation. The present patient underwent a computed tomography scan of the head that showed diffuse abnormalities of the white matter, with abnormally low density in the thalamus and midbrain, consistent with a diagnosis of Cree leukoencephalopathy. Cree leukoencephalopathy is an autosomal recessive leukodystrophy of unknown cause that affects the Cree populations of northern Quebec and Manitoba (1). It is characterized by an acute or subacute neurological deterioration, usually in the setting of a febrile illness. Diffuse and symmetrical hypoattenuation of the white matter in the cerebrum and cerebellum is seen on neuroimaging. Death is the eventual outcome in all patients (2). Children with Cree leukoencephalopathy have normal development through the first few months of life. They later experience some vague behavioural changes that are usually not significant enough to be brought to medical attention. They then experience a nonspecific febrile illness, usually a viral infection, and within a short period of time, they become either hypotonic or show signs of spasticity, and they develop seizures, eye deviation and abnormal posturing (3). Their clinical condition usually worsens over days to weeks, and they become increasingly irritable, continue to have abnormal posturing and seizures, and eventually die. There may be evidence of autonomic dysfunction (loss of the pupillary reflex, urinary retention and intestinal atony) in some cases (2). There is usually a first-degree relative or a more distant relative who was previously diagnosed with the same disease. In many cases, there have been affected siblings. The diagnosis is confirmed by clinical signs, a family history and the distinct changes seen on head computed tomography or magnetic resonance imaging. Cree leukoencephalopathy is pathologically distinct from other leukodystrophies. There are no consistent cerebrospinal fluid, serum amino acid or urine organic acid abnormalities (2). On autopsy, there is a diffuse loss of cerebral myelin, an absence of intracellular storage products and an absence of inflammation (3). Recently, Cree leukoencephalopathy has been linked to central hypomyelination syndrome/vanishing white matter (1). Prenatal genetic testing is now available to affected families (M Lefson, personal communication). The differential diagnosis for a child with a neurodegenerative disease is extensive. Disorders affecting gray matter (eg, Tay-Sachs disease) can present with a loss of cognitive abilities, seizures or pigmentary changes of the retina (4). Most diseases of the white matter are demyelinating disorders called leukodystrophies (eg, metachromatic leukodystrophy). Persons with these disorders usually present with spasticity, seizures and optic atrophy. There are many other disorders that can mimic neurodegenerative diseases, such as hypothyroidism, tumours, and congenital or acute infections (4). In most cases, the exact etiology is not clear, and biochemical disorders, infectious causes and inflammatory disorders must be considered. Brain imaging is an essential part of the diagnostic workup for degenerative disorders. Further testing may be warranted depending on the clinical presentation. In the present case, a lumbar puncture was eventually performed, which showed normal results with a negative culture. All hematological and biochemical studies were normal. He continued to have tremors but no clear seizures. An electroencephalogram showed no epileptiform activity. He was eventually extubated and weaned from sedation. He was very spastic neurologically, had poor eye contact and was very irritable. No further studies were performed at this point. His diagnosis and prognosis were discussed with the family and they requested that he be transferred home. He was transferred back to the hospital in his village, where he continued to deteriorate. One week later, he passed away, surrounded by his entire extended family. Cree leukoencephalopathy is an autosomal recessive leukodystrophy characterized by an acute or subacute deterioration in the setting of a febrile illness. Diagnosis is based on clinical findings, family history and typical changes on neuroimaging. Physicians working with Aboriginal children should be aware of health care issues unique to this population (eg, Cree leukoencephalopathy). Getting a complete history is critically important, which highlights the importance of Native-speaking health care workers and the value of the extended family in getting essential information. The case presentation should not exceed 200 words and should give the reader enough information to suspect the diagnosis without making it obvious. The discussion should not exceed 600 words and should be followed by a couple of ‘clinical pearls’. A maximum of two references may be included, if helpful. The submitted cases will undergo peer review and revision at the discretion of the editors. Priority is given to cases illustrating an approach to common problems or important clinical clues to less common diagnoses that should not be missed. The Editorial Board hopes that this provides an opportunity for trainees and paediatricians practising outside of the teaching hospitals to share their clinical experiences and to publish in Paediatrics & Child Health. If you have a case to submit, contact Dr Friedman by e-mail at jeremy.friedman@sickkids.ca.

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