CADASIL

Natural History

CADASIL is a microangiopathy mainly affecting the brain. The presenting symptoms, age at onset, and disease progression in CADASIL vary.

Stroke-like episodes. Transient ischemic attacks (TIAs) and stroke, the most frequent presentation, are found in approximately 85% of symptomatic individuals [Dichgans et al 1998]. Strokes related to small vessel pathology are clearly the main manifestation of the disease.

Mean age at onset for ischemic episodes is approximately 46 years (age range: ~19-67 years) [Opherk et al 2004].

Ischemic episodes typically present as a classic lacunar syndrome (pure motor stroke, ataxic hemiparesis/dysarthria-clumsy hand syndrome, pure sensory stroke, sensorimotor stroke), but other lacunar syndromes (brain stem or hemispheric) are also observed. Ischemic episodes are often recurrent, leading to severe disability with gait disturbance, urinary incontinence, and pseudobulbar palsy.

Strokes involving the territory of a large artery have occasionally been reported. However, those observations may be coincidental.

Cognitive deficits and dementia. Cognitive deficits, the second most frequent feature, are observed in approximately 60% of symptomatic individuals. They may start as early as age 35 years. Approximately 75% of affected individuals develop dementia [Dichgans et al 1998, Opherk et al 2004, Dichgans 2009].

The pattern of cognitive dysfunction is characterized by deficits in executive function (timed measures and measures of error monitoring), verbal fluency, and memory with benefit from clues [Peters et al 2005b]. Cognitive dysfunction is accompanied by a narrowing of the field of interest. In most cases, cognitive decline is slowly progressive with additional stepwise deterioration. Amberla et al [2004] observed deterioration of working memory and executive function in individuals with NOTCH3 mutations in the prestroke phase, and infer that cognitive decline may start insidiously before the onset of symptomatic ischemic episodes.

Migraine. Migraine occurs in approximately 35% of individuals with CADASIL, with the first attack occurring at a mean age of 26 years. Ninety percent of individuals with migraine have migraine with aura [Dichgans et al 1998]. In some families with CADASIL, migraine with aura is the most prominent symptom.

Reversible acute encephalopathy. Acute encephalopathy has been described in approximately a dozen individuals, with confusion, headache, pyrexia, seizures, and coma, sometimes leading to death [Feuerhake et al 2002, Schon et al 2003].

Psychiatric disorders. Thirty percent of individuals with CADASIL experience psychiatric disturbance, varying from personality changes to severe depression [Dichgans et al 1998]. Whether these disturbances are primary or reactive is not yet clear. However, individuals with CADASIL presenting with psychiatric problems have been described [Leyhe et al 2005, Nakamura et al 2005].

Epilepsy. Epilepsy is present in 10% of individuals with CADASIL and presents at middle age [Dichgans et al 1998].

Pregnancy. A retrospective study of 25 women found an increased frequency of ischemic symptoms (TIA and stroke) during pregnancy and puerperium (the period between childbirth and the return of the uterus to its normal size), particularly in those older than age 30 years [Roine et al 2005].

Other

• Cardiac involvement. Controversy exists as to whether CADASIL is associated with cardiac involvement. In a study from The Netherlands, nearly 25% of individuals with NOTCH3 mutations had a history of acute myocardial infarction (MI) and/or current pathologic Q-waves on electrocardiogram [Lesnik Oberstein et al 2003]. This percentage was significantly higher than in controls without a NOTCH3 mutation. However, another study of 23 individuals with a NOTCH3 mutation found no signs of previous MI on ECG [Cumurciuc et al 2006].

• Subclinical peripheral neuropathy has been reported in some individuals [Schroder et al 2005, Sicurelli et al 2005].

• Ocular findings. Subclinical retinal lesions are reported [Cumurciuc et al 2004]. Fundoscopy may reveal clinically silent retinal vascular abnormalities [Haritoglou et al 2004].