Neurologic Findings in Patients With Sickle Cell Disease

Sickle cell disease (SCD) is a monogenic disorder due to a alteration in the β-globin gene resulting in the substitution of the amino acid valine for glutamic acid in the β-globin chain.¹ In the deoxygenated state, this variation leads to polymerization of sickle hemoglobin and subsequent red cell sickling with cycles of macrovascular and microvascular vaso-occlusion, end-organ ischemia, reperfusion injury, and infarction. SCD is truly multisystemic in impact. Sickling and vaso-occlusion is the predominant—but not the only—underlying mechanism for the chronic pain that often dominates the lives of these patients, especially in low- and middle-income countries.² Despite improving treatments, life expectancy is still almost 20 years shorter than in the general population, and especially so in low-income countries.³

Although initially restricted to sub-Saharan Africa and the Indian subcontinent where it evolved as a protective mechanism against malaria, the disease is now global and has been declared a public health burden by the World Health Organization (WHO).⁴ The prevalence of the disease at birth is expected to rise because of improving survival and increasing migration to higher-income countries.⁵

Neurologic complications are abundant in SCD, with stroke being the most devastating and best-known complication. Other common neurologic complications include epilepsy,⁶ peripheral mononeuropathies and polyneuropathies,⁷ neuropathic pain,⁸ cognitive dysfunction, and ocular complications,⁹ with abnormal neurologic findings that can be corroborated by imaging and other investigative modalities.

In this issue of Neurology® Clinical Practice, Nawaiseh et al.¹⁰ describe the presence of abnormal neurologic findings on clinical examination of SCD patients without a history of major neurologic events. This study identified several abnormalities in the examination including abnormal reflexes, gait abnormalities, cerebellar dysfunction, language deficits, nystagmus, abnormal muscle tone and strength, Romberg sign, Horner syndrome, and intellectual impairment, which were present in 14.5% of all 3573 patients evaluated. It also identified a history of eye disease and osteomyelitis as the main predictors of an abnormal examination, with smoking, the hand-foot syndrome, aseptic necrosis, male sex, overweight status, elevated blood pressure, and older age as additional predictors. The authors emphasize that careful physical examinations and risk factor identification might contribute significantly to improved management of these patients, particularly in low-income underresourced settings where indeed the great majority of patients with SCD live. They suggest that while further confirmatory work is necessary with prospective study designs and more comprehensive imaging, clinicians managing these patients should now pay more attention to history and examination findings and to risk factor modification, especially encouraging smoking cessation, as ways of predicting and, potentially, preventing neurologic decline.

Noted by Nawaisah et al. was the lack of close concordance between the presence or absence of MRI abnormalities (performed in only 92 patients [2.5%]) and the presence or absence of abnormal neurologic findings in this retrospective and multicentered study.¹⁰ The paper addresses this by noting that some of these abnormalities would not have abnormalities on neuroimaging but would, for example, be supported by appropriate evaluations for peripheral neuropathies, namely, clinical neurophysiology. Here, the old guidance remains relevant: clinical neurophysiology, if available, is an extension of the clinical examination and rests on a reliable neurologic examination. They appropriately suggest that prospective studies would also help by standardizing the neurologic examination thereby ensuring higher quality physical examination findings, helping to more accurately confirm—or refute—these stated associations. Physical examinations should also include careful examination of the optic nerve and retina, recognizing that fundoscopy can permit visualization of processes affecting the CNS.

Although a physical examination may seem inexpensive and easily implementable in a low-resourced environment, the time to complete this properly is often a major factor. In addition, a detailed neurologic examination is not usually the priority when these patients are seen in the urgent or emergent setting which is usually for an acute nonneurologic problem, such as acute chest syndrome or acute painful crisis. Indeed, the physicians managing these patients are also not usually neurologists.

The shortage, in many parts of the world, of technologies such as transcranial Doppler to predict risk of stroke and of MRI to evaluate for silent cerebral infarcts means that routine use of these technologies may not always be feasible. Indeed, these tests may also have to be paid for out-of-pocket in many resource-constrained environments. The clinical predictors of high risk postulated by Nawaiseh et al. may help physicians use scarce resources more pragmatically but may require training to reliably elicit these bedside clinical signs.

Finally, there are several SCD genotypes in different populations of the world. In addition to these disease genetic variations, there are genetic differences in the various populations affected by this disorder and, additionally, epigenetic modulators related to the effect of local environmental and behavioral factors can have a significant influence on disease expression, sometimes also resulting in a much-altered clinical phenotype, including a lower risk of stroke. Awareness of this clinical heterogeneity is important for neurologists who may increasingly be required to participate in the care of these patients. Finally, as longevity for patients with SCD has increased, chronic disease comorbidities may also have their own effects on the neurologic system just like in the general population. These must be carefully distinguished from the effects of SCD, for example, the arthritic antalgic gait from a neurologic gait.

This paper by Nawaiseh et al. cogently serves to remind that old-fashioned clinical neurology remains relevant and is at its most elegant when used in combination with appropriately applied technologies that are best chosen by carefully documented neurologic histories and examinations. This sequential rigor will be most impactful, from an efficiency and cost-saving perspective, in underresourced environments, whether in the developing world or, indeed, in many parts of North America, where the population of patients with SCD continues to grow.

Study Funding

The authors report no targeted funding.

Disclosure

Honoraria from Roche Pharma for speaking engagements (Multiple Sclerosis). Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.