Cadasil coma: Unusual cause for acute encephalopathy.

Sir,

We report a 24-year-old male who presented to us with 5-days history of fever and severe throbbing headache which eventually progressed over next 2 days to an acute encephalopathy. On examination, he was disoriented to time and place. He had left hemiparesis with increased tone on left side and bilateral extensor plantar. There was no neck stiffness. Within a day of admission, he deteriorated further and responded only to painful stimuli. He was shifted to intensive care unit (ICU) and ventilated. He developed three episodes of generalized tonic clonic seizures. His routine blood tests and cerebrospinal fluid (CSF) analysis were within normal limits. CSF sent for gram stain, culture, herpes simplex virus polymerase chain reaction (HSV PCR), and tuberculosis polymerase chain reaction (TB PCR) were negative. We made an empirical diagnosis of viral encephalitis and treated him with acyclovir, antibiotics and antiepileptics. His magnetic resonance imaging (MRI) brain showed diffuse periventricular T2/FLAIR white matter hyperintensity [Figures 1 and 2] with a normal MR angiogram. Electroencephalography (EEG) showed bilateral diffuse delta range slow waves. During the next 3 days in ICU despite our best measures, patient developed pneumonia, sepsis, and died. We got an interesting history of similar illness in his mother and grandfather. Both of them suffered from recurrent episodic headaches and strokes which progressed to dementia. Patient was also suffering from migraine with visual aura since childhood. On reviewing his MRI, we found anterior temporal lobe and external capsule involvement characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We confirmed the diagnosis with molecular genetic testing for notch3 mutation sequenced from exons 2, 3, 4, 5, and 6. Results were positive for heterozygous mutation for p. C144s.

Figure 1

MRI FLAIR shows periventricular white matter hyperintensity

Figure 2

MRI FLAIR shows anterior temporal lobe involement

CADASIL is a genetic disorder caused by mutations in the NOTCH3 gene in chromosome 19. It is characterized by migraine with aura, repeated lacunar strokes, and dementia.[1] Acute encephalopathy like presentation is known to occur in CADASIL. This is a very rare type of presentation called as CADASIL coma. F Schon et al. described six cases presenting with acute encephalopathic illness in a series of 70 cases of CADASIL. But unlike our case all six fully recovered over a period of 1-2 weeks.[2] Chabriat et al. reported a family who presented with CADASIL coma and one of the family member died over a week similar to our case.[3] Kors et al. described similar cases of coma following trivial head trauma in patients with familial hemiplegic migraine (FHM) which is again characterized by migraine with aura. Both FHM and CADASIL are due to different gene defects located in same chromosome 19. They postulated that coma was due to diffuse cerebral edema.[4] But the exact cause for CADASIL coma is unknown. Feuerhake F et al. hypothesized that transient disturbance of the blood-brain barrier related to the underlying vascular pathology may have caused this unusual presentation. They postulated based on brain biopsy from their patient which revealed typical vascular changes of CADASIL, subtle endothelial alterations, white matter edema and reactive gliosis.[5]

In conclusion, CADASIL is a rare inherited disease characterized by stroke and migraine. Acute encephalopathy like presentation in CADASIL is called CADASIL coma. It should be considered as an important differential diagnosis for patients presenting with acute encephalopathy. Important clue to diagnosis lies in family history, migraine and MRI features.