We thank our readers for all their enthusiasm with this case challenge. Most of you have made the correct diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In this second part of the case presentation, we comment on how to work up the case and do a differential diagnosis with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
The 58-year-old man presenting with migraine and behavioral changes, presented on September 12, 2017, had genetic analysis, which revealed a R141C mutation in exon 4 in the NOTCH3 gene. Pharmacologic therapy (with acetazolamide 250 mg BID and acetylsalicylic acid 300 mg QD) was continued. Symptomatic treatment with escitalopram 10 mg QD was begun. At follow-up visits, the patient's symptoms remained stable.
Comment
In this patient a history of mood disorders, cognitive impairment, migraine, recurrent strokes, and a positive NOTCH3 gene mutation suggested a CADASIL disorder (BMC Med 2017; 15:41). This type of hereditary cerebral small vessel disease has a monogenic cause that involves the NOTCH3 gene, which is located in the short arm of chromosome 19 and encodes for a transmembrane receptor protein that is usually expressed in vascular smooth muscle cells (VSMCs) and pericytes. Mutations affect the extracellular portion of the coded protein and lead to the deposition and accumulation of granular osmiophilic material (GOM) in the plasma membrane of VSMCs and pericytes (Curr Pain Headache Rep 2017; 21:21). Arterial contractility and vasomotor function are eventually impaired by wall thickening and stenosis of small arteries.
Clinical presentation can vary within affected patients. However, the main signs and symptoms include migraine with aura, subcortical ischemic events, cognitive impairment, and mood changes. Migraine with aura is generally the first symptom and is five times more prevalent in these patients than in the general population (Lancet Neurol 2009; 8:643). Transient ischemic attacks and recurrent strokes are the most frequent symptom and lead to lacunar syndromes and significant cognitive decline. Dementia and cerebrovascular disease are the main causes of morbidity and mortality in these patients (Continuum [Minneap Minn] 2014; 20:399). Mood disturbances are mainly severe depression, apathy, and occasional manic episodes that can be mistaken for psychiatric diseases before the diagnosis is confirmed.
The differential diagnosis between CADASIL and CARASIL has been claimed not to rely on molecular genetic analysis but on differentiation of clinical signs and symptoms. Symptom onset in CARASIL is approximately 10 to 15 years earlier than in CADASIL. Because of the recessive pattern of inheritance in CARASIL, memory dysfunction appears to be more severe. Also, premature diffuse baldness can occur, predominantly in male patients in the second decade of life. Connective tissue is frequently affected; nearly 80% of patients complain of low back pain, which usually correlates with magnetic resonance imaging (MRI) findings such as disk herniation and spondylosis deformans, at thoracic and upper lumbar levels (Brain Pathology 2014; 24:525 and J Stroke Cerebrovasc Dis 2011; 20:85).
MRI is the mainstay in the radiologic evaluation of CADASIL. Common neuroimaging findings include extensive white matter abnormalities and lacunes that usually precede the onset of symptoms by many years. T2 hyperintensities affecting the white matter of the anterior temporal poles (O'Sullivan sign) have a sensitivity and specificity of about 90% for CADASIL. In contrast, such a finding is uncommon in sporadic small vessel disease. As seen in our patient, lesions in the extreme capsule and corpus callosum are other characteristic features. However, the presence of callosal lesions may lead to a misdiagnosis of multiple sclerosis. Microhemorrhages and brain atrophy, although frequently present, are not specific for CADASIL (BMC Med 2017; 15:41; NEJM Journal Watch Neurol Jan 24 2002; [e-pub]).
More than 200 NOTCH3 mutations have been described, most of them involving missense substitutions of a single base that lead to the gain or loss of a cysteine residue in one extracellular domain of the protein. Full screening of all exons of the extracellular growth factor-like repeats increases sensitivity and specificity to 95%; however, false-negative results can still be seen. Considering that GOM deposits can also be detected in extracerebral vessels of tissues like skin and muscle, when the NOTCH3 mutation result is negative and clinical suspicion is still high, skin biopsy is recommended (BMC Med 2017; 15:41).
No specific treatment is available for CADASIL. Nevertheless, symptoms and risk factors can be addressed. In a case of migraine with aura that might require prophylaxis, the usual therapy with antiepileptic drugs and beta-blockers can be initiated. In the acute setting, although vasoconstrictors should be avoided, triptans may be safe. Vascular risk factors should be treated with statins and antiplatelet medications rather than with anticoagulants because of the increased risk for hemorrhage. For cognitive impairment and dementia, treatment is still controversial. A multidisciplinary approach is important in order to rehabilitate and maintain quality of life for these patients (Lancet Neurol 2009; 8:643 and Continuum [Minneap Minn] 2014; 20:399).
Authors
DisclosuresEditorial BoardsMultiple Sclerosis and Related Disorders
DisclosuresEditorial BoardsMultiple Sclerosis and Related Disorders
Comment
In this patient a history of mood disorders, cognitive impairment, migraine, recurrent strokes, and a positive NOTCH3 gene mutation suggested a CADASIL disorder (BMC Med 2017; 15:41). This type of hereditary cerebral small vessel disease has a monogenic cause that involves the NOTCH3 gene, which is located in the short arm of chromosome 19 and encodes for a transmembrane receptor protein that is usually expressed in vascular smooth muscle cells (VSMCs) and pericytes. Mutations affect the extracellular portion of the coded protein and lead to the deposition and accumulation of granular osmiophilic material (GOM) in the plasma membrane of VSMCs and pericytes (Curr Pain Headache Rep 2017; 21:21). Arterial contractility and vasomotor function are eventually impaired by wall thickening and stenosis of small arteries.
Clinical presentation can vary within affected patients. However, the main signs and symptoms include migraine with aura, subcortical ischemic events, cognitive impairment, and mood changes. Migraine with aura is generally the first symptom and is five times more prevalent in these patients than in the general population (Lancet Neurol 2009; 8:643). Transient ischemic attacks and recurrent strokes are the most frequent symptom and lead to lacunar syndromes and significant cognitive decline. Dementia and cerebrovascular disease are the main causes of morbidity and mortality in these patients (Continuum [Minneap Minn] 2014; 20:399). Mood disturbances are mainly severe depression, apathy, and occasional manic episodes that can be mistaken for psychiatric diseases before the diagnosis is confirmed.
The differential diagnosis between CADASIL and CARASIL has been claimed not to rely on molecular genetic analysis but on differentiation of clinical signs and symptoms. Symptom onset in CARASIL is approximately 10 to 15 years earlier than in CADASIL. Because of the recessive pattern of inheritance in CARASIL, memory dysfunction appears to be more severe. Also, premature diffuse baldness can occur, predominantly in male patients in the second decade of life. Connective tissue is frequently affected; nearly 80% of patients complain of low back pain, which usually correlates with magnetic resonance imaging (MRI) findings such as disk herniation and spondylosis deformans, at thoracic and upper lumbar levels (Brain Pathology 2014; 24:525 and J Stroke Cerebrovasc Dis 2011; 20:85).
MRI is the mainstay in the radiologic evaluation of CADASIL. Common neuroimaging findings include extensive white matter abnormalities and lacunes that usually precede the onset of symptoms by many years. T2 hyperintensities affecting the white matter of the anterior temporal poles (O'Sullivan sign) have a sensitivity and specificity of about 90% for CADASIL. In contrast, such a finding is uncommon in sporadic small vessel disease. As seen in our patient, lesions in the extreme capsule and corpus callosum are other characteristic features. However, the presence of callosal lesions may lead to a misdiagnosis of multiple sclerosis. Microhemorrhages and brain atrophy, although frequently present, are not specific for CADASIL (BMC Med 2017; 15:41; NEJM Journal Watch Neurol Jan 24 2002; [e-pub]).
More than 200 NOTCH3 mutations have been described, most of them involving missense substitutions of a single base that lead to the gain or loss of a cysteine residue in one extracellular domain of the protein. Full screening of all exons of the extracellular growth factor-like repeats increases sensitivity and specificity to 95%; however, false-negative results can still be seen. Considering that GOM deposits can also be detected in extracerebral vessels of tissues like skin and muscle, when the NOTCH3 mutation result is negative and clinical suspicion is still high, skin biopsy is recommended (BMC Med 2017; 15:41).
No specific treatment is available for CADASIL. Nevertheless, symptoms and risk factors can be addressed. In a case of migraine with aura that might require prophylaxis, the usual therapy with antiepileptic drugs and beta-blockers can be initiated. In the acute setting, although vasoconstrictors should be avoided, triptans may be safe. Vascular risk factors should be treated with statins and antiplatelet medications rather than with anticoagulants because of the increased risk for hemorrhage. For cognitive impairment and dementia, treatment is still controversial. A multidisciplinary approach is important in order to rehabilitate and maintain quality of life for these patients (Lancet Neurol 2009; 8:643 and Continuum [Minneap Minn] 2014; 20:399).