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Mark Walterfang, FRANZCP, Level 2, John Cade Building, Royal Melbourne Hospital, Melbourne 3050, Australia. Email: firstname.lastname@example.org
Abstract Langerhan’s cell histiocytosis (LCH) has been described as a progressive neurological disorder marked by neurological and cognitive decline. The authors here report a case of a childhood LCH sufferer who made a significant recovery of neuropsychological function in the absence of motor recovery in late adolescence. This differential recovery of motor and cognitive functioning may relate to the interaction between LCH and childhood and adolescent neurodevelopmental processes.
Langerhans’ cell histiocytosis (LCH), previously known as ‘histiocytosis X’, is a disorder of uncontrolled clonal proliferation of Langerhans’ cells1 and encompasses a continuum of clinical entities ranging from a solitary bone lesion to a multisystem life-threatening disorder.2 Some reports have suggested that central nervous system (CNS) involvement is associated with progressive general intellectual decline and more specific deficits of attention and memory.3,4 Here, the authors describe the case of an adult male with lifelong LCH who demonstrated initial neuropsychological impairments, which improved over time.
A 20-year-old man with known LCH was referred with a history of behavioral difficulties and non-compliance with LCH therapy. Neuropsychiatric opinion was sought to ascertain whether these issues were related to a direct effect of LCH on brain function, and the impact of potential progressive decline on competency to make decisions regarding medical and financial affairs.
The patient had presented at 11 months of age with recurrent dermatitis and mouth ulceration, and was diagnosed with LCH on biopsy. He commenced a course of chemotherapy with intravenous vincristine, oral prednisolone, methotrexate and cyclophosphamide. At 3 years of age he presented with lytic lesions in his skull and palate, and was treated with oral etoposide. At 6 years of age he developed several new lytic skull lesions, again treated with etoposide. Occipital skull recurrence at 13 years of age was treated with methotrexate and prednisolone. Following two spontaneous pneumothoraces at the age of 18, lung biopsy and respiratory function tests were consistent with LCH-related interstitial lung disease.
The patient had normal motor and cognitive development until aged 9 when he developed dysarthria and clumsiness. At age 13, magnetic resonance imaging was undertaken to investigate prominent cerebellar and pyramidal leg signs, and revealed bilaterally increased T2 signal in the dentate nucleus and T2 hyperintensity in left parietal deep white matter. Chromosomal screening, testing of fatty and organic acids, and screens for lysosomal disorders and spinocerebellar atrophy were normal.
Neuropsychological testing at aged 14 using the Wechsler Intelligence Scale for Children (WISC-III)5 found the patient to be performing in the mildly intellectually disabled range overall, with stronger verbal intellectual functioning (borderline range) compared to non-verbal/performance abilities (mildly intellectually disabled range). The WISC-III together with additional neuropsychological tests identified that he showed slowed processing in particular, but demonstrated good immediate auditory and spatial attention span, and well-developed memory and learning skills across domains. Executive deficits in relation to organization, planning and impulse control were also identified.
Repeat neuropsychological testing 2 years later at the age of 17 with the Wechsler Adult Intelligence Scale (WAIS-III) revealed an overall significant improvement in general intellectual functioning to the low average range of ability. Processing speed remained slow, and again on further testing he was found to be demonstrating strong verbal memory and learning skills, and average non-verbal memory abilities. Executive functioning was variable with some intact skills (reasoning and verbal fluency) but ongoing deficits in relation to planning and organization, and mental flexibility. Executive functioning was otherwise intact.
At age 20, the patient was noted to be of small stature with signs of fibrotic lung disease and severe cerebellar disease with dysarthric, scanning speech, truncal and gait ataxia. The most notable magnetic resonance imaging finding was moderate cerebellar atrophy, seen on Fig. 1, with no evidence of hypothalamic infiltration. A single photon emission computed tomography scan was reported as normal (Fig. 2).
On the WAIS-III, the patient performed in the low average range on both the verbal-comprehension index and the perceptual-organization index. This supported the previous assessment in representing a statistically significant improvement in his intellectual skills since his childhood testing. Immediate auditory attention span was within normal limits and he showed a significant strength in relation to memory and learning abilities, which had also been identified on his past assessments. In particular, his immediate and delayed recall of verbal prose was in the superior range. Verbal learning skills fell in the average range, and he was able to adequately retain information in memory over time. In the non-verbal domain, his recall of visuospatial designs was similarly intact (high average range) and again retained in memory over time (average range). Slowed processing remained problematic, and he continued to demonstrate higher level mental flexibility, planning and organizational difficulties. The patient’s verbal and non-verbal performance over time is shown in Fig. 3.
Central nervous system involvement of LCH is most commonly associated with granulomatous infiltration of the hypothalamus, cerebellum and basal ganglia6 but may involve all parts of the CNS as space-occupying or infiltrative, inflammatory changes.3 Space occupying lesions result from granulomatous accumulation of histiocytes, whereas infiltrative lesions are associated with a neuro-inflammatory process driven by T-cells which results in demyelination, neuronal loss and gliosis.7
Relatively little is known about the cognitive profile of LCH sufferers as few reports of detailed neuropsychological testing have been published. The largest study assessed 28 long-term survivors of childhood LCH on neuropsychological and neuroradiological measures. The majority of patients had cerebellar dysfunction as illustrated by demonstrable ataxia which was rated as severe in half of the group.4 Patients with non-hypothalamic CNS involvement (signal change in cerebellar hemispheres/dentate nuclei, hydrocephalus, cerebral atrophy, or dural thickening) were markedly impaired in verbal, performance and full-scale intelligence quotient (IQ) compared to those with hypothalamic involvement alone or no intracranial pathology. Marked deficits were also identified in attention, visual memory, and managing verbal interference, whilst basic language and other academic abilities were intact in the CNS-affected group. The only report of longitudinal neuropsychological function in LCH, of an adolescent with significant cerebellar involvement assessed at 12 and 15 years, showed a significant decline in verbal and performance IQ, with full-scale IQ dropping from 112 to 86 over the 3 year interval.8
It has been suggested that LCH sufferers with cerebellar changes generally show a progressive clinical and neurological decline,3,8–10 and LCH has been described as ‘a progressive neuropsychiatric disease’.9 The evidence for cognitive decline is, however, lacking, with a single case report constituting the evidence base. In contrast, the current patient demonstrated a different pattern of impairment to those reported in the literature, in spite of clinically and neuroradiologically confirmed non-hypothalamic CNS involvement of his disease. Whilst he showed low-average global intellectual function, contrary to the published case reports conveying reduced attentional capacity and variable memory performance, his immediate auditory attention span was sound and memory was a consistent strength across verbal and non-verbal domains. In addition, whereas he performed poorly on general intellectual assessment in early adolescence, there was a significant global intellectual improvement over subsequent years without any comparable improvement in motor function. Some deficits persisted across assessments, particularly in information processing speed, planning, organization and mental flexibility, whilst other executive functions have remained intact.
The reasons for this differential improvement in cognitive but not motor function are unclear. It is possible that this represents a change in disease activity and, therefore, recovery of some functions of the CNS, or differential effects of disease activity on different CNS structures. A further possibility considers that LCH often presents with neuropsychiatric impairment during childhood and adolescence, and, therefore, stands to disrupt a range of neurodevelopmental processes. Reduced disease activity in mid-adolescence could permit some interrupted neurodevelopmental processes to resume, such as those involved in some cognitive processes, and, therefore, an apparent cognitive ‘recovery’ could occur in the absence of recovery of the motor system, whose neurodevelopmental trajectory was close to complete at the time of onset of LCH.
Given that there is little evidence to suggest that chemotherapeutic treatments used for LCH (such as etoposide and methotrexate, used in the current patient) are associated with significant neurotoxicity,11 it is possible that early detection and treatment of LCH-related CNS disease could significantly alter the course of the disease and permit ‘cognitive recovery’ in late adolescence/early adulthood. Study of the longitudinal effects of illness activity and treatment on neuropsychological function is warranted in larger cohorts to determine if this is the case, as identifying this potential for improvement is essential to ensure optimum outcomes for sufferers of LCH.